5-substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)-and 3-(piperidin-4-yl)-1h-indoles: 5-HT1F agonists

ABSTRACT

This invention provides novel 5-HT 1F  agonists of Formula I ##STR1## where A--B, R,R 1  and X are as defined in the specification, which are useful for the treatment of migraine and associated disorders.

CROSS-REFERENCE

This application is a division of application Ser. No. 08/619,783 filedMar. 20, 1996, now U.S. Pat. No. 5,708,008, which is acontinuation-in-part of copending application U.S. Ser. No. 08/407,553,filed Mar. 20, 1995, now abandoned.

BACKGROUND OF THE INVENTION

Theories regarding the pathophysiology of migraine have been dominatedsince 1938 by the work of Graham and Wolff (Arch. Neurol. Psychiatry,39, 737-63 (1938)). They proposed that the cause of migraine headachewas vasodilatation of extracranial vessels. This view was supported byknowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT₁agonist which does not cross the blood-brain barrier, contract cephalicvascular smooth muscle and are effective in the treatment of migraine.(Humphrey, et al., Ann. NY Acad. Sci., 600, 587-600 (1990)). Recent workby Moskowitz has shown, however, that the occurrence of migraineheadaches is independent of changes in vessel diameter (Cephalalgia, 12,5-7, (1992)).

Moskowitz has proposed that currently unknown triggers for painstimulate trigeminal ganglia which innervate vasculature within thecephalic tissue, giving rise to release of vasoactive neuropeptides fromaxons on the vasculature. These released neuropeptides then activate aseries of events, a consequence of which is pain. This neurogenicinflammation is blocked by sumatriptan and ergot alkaloids by mechanismsinvolving 5-HT receptors, believed to be closely related to the5-HT_(1D) subtype, located on the trigeminovascular fibers (Neurology,43(suppl. 3), S16-S20 (1993)).

Serotonin (5-HT) exhibits diverse physiological activity mediated by atleast seven receptor classes, the most heterogeneous of which appears tobe 5-HT₁. A human gene which expresses one of these 5-HT₁ receptorsubtypes, named 5-HT_(1F), was isolated by Kao and coworkers (Proc.Natl. Acad. Sci. USA, 90, 408-412 (1993)). This 5-HT_(1F) receptorexhibits a pharmacological profile distinct from any serotonergicreceptor yet described. The high affinity of sumatriptan at thissubtype, K_(i) =23 nM, suggests a role of the 5-HT_(1F) receptor inmigraine.

This invention provides novel 5-HT_(1F) agonists which inhibit peptideextravasation due to stimulation of the trigeminal ganglia, and aretherefore useful for the treatment of migraine and associated disorders.

SUMMARY OF THE INVENTION

The present invention provides novel5-substituted-3-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles and5-substituted-3-(piperidin-4-yl)-1H-indoles of Formula I: ##STR2## inwhich A--B is --CH--CH₂ -- or --C═CH--;

R is H or C₁ -C₆ alkyl;

R¹ is H or C₁ -C₄ alkyl;

X is --S--R², --C(O)R³, --C(O)NR⁴ R¹⁵, --NR⁵ R⁶, --NR⁷ SO₂ R⁸,--NHC(Q)NR¹⁰ R¹¹, --NHC(O)OR¹² or --NR¹³ C(O)R¹⁴ ; where

Q is O, or S;

R² is phenyl, substituted phenyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄alkylene) substituted in the phenyl ring, or pyridinyl;

R³ is C₁ -C₆ alkyl, phenyl(C₁ -C₄ alkylene), phenyl (C₁ -C₄ alkylene)substituted in the phenyl ring, naphthyl, N-methyl-N-methoxyamino,heteroaryl, substituted heteroaryl, heteroaryl(C₁ -C₄ alkyl), orsubstituted heteroaryl(C₁ -C₄ alkyl);

R⁴ is heteroaryl, substituted heteroaryl, heteroaryl(C₁ -C₄ alkyl), orsubstituted heteroaryl(C₁ -C₄ alkyl);

R⁴ and R¹⁵ taken together with the nitrogen atom form a pyrrolidine,piperidine, substituted piperidine, piperazine, 4-substitutedpiperazine, morpholine or thiomorpholine ring;

R⁵ and R⁶ are both trifluoromethanesulfonyl;

R⁷ is H or C₁ -C₄ alkyl;

R⁸ is C₁ -C₄ alkyl, phenyl, substituted phenyl, or di(C₁ -C₄alkyl)amino;

R¹⁰ and R¹¹ are independently selected from the group consisting of C₁-C₆ alkyl, C₃ -C₆ alkenyl, C₃ -C₈ cycloalkyl, phenyl, substitutedphenyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄ alkylene) substituted inthe phenyl ring, ((C₁ -C₄ alkyl or C₁ -C₄ alkoxycarbonyl substituted)C₁-C₄ alkyl)phenyl, C₁ -C₄ alkyl α-substituted with C₁ -C₄ alkoxycarbonyl;or

R¹⁰ and R¹¹ taken together with the nitrogen atom form a pyrrolidine,piperidine, piperazine, 4-substituted piperazine, morpholine orthiomorpholine ring;

R¹² is C₁ -C₆ alkyl, C₃ -C₆ alkenyl, phenyl, substituted phenyl, C₃ -C₈cycloalkyl, C₁ -C₄ alkyl ω-substituted with C₁ -C₄ alkoxy;

R¹³ is H or C₁ -C₄ alkyl;

R¹⁴ is C₁ -C₁₀ alkyl substituted with up to three substituents selectedfrom the group consisting of hydroxy, C₁ -C₄ alkoxy, halo, aryloxy, C₁-C₄ alkoxycarbonyl and heteroaryloxy, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl,C₃ -C₈ cycloalkyl, phenyl, substituted phenyl, naphthyl, phenyl(C₁ -C₄alkylene), phenyl(C₁ -C₄ alkylene) substituted on the phenyl ring,2-phenylethylen-1-yl, diphenylmethyl, benzofused C₄ -C₈ cycloalkyl, C₁-C₄ alkylene (ω-substituted with C₃ -C₆ cycloalkyl, or a heterocycle;

R¹⁵ is H or C₁ -C₆ alkyl;

subject to the proviso that when R⁷ is H, R⁸ is not C₁ -C₄ alkyl; andpharmaceutically acceptable acid addition salts and solvates thereof.This invention also provides a pharmaceutical formulation whichcomprises, in association with a pharmaceutically acceptable carrier,diluent or excipient, a compound of Formula I.

A further embodiment of this invention is a method for increasingactivation of the 5-HT_(1F) receptor for treating a variety of disorderswhich have been linked to decreased neurotransmission of serotonin inmammals. Included among these disorders are depression, migraine pain,bulimia, premenstrual syndrome or late luteal phase syndrome,alcoholism, tobacco abuse, panic disorder, anxiety, general pain,post-traumatic syndrome, memory loss, dementia of aging, social phobia,attention deficit hyperactivity disorder, disruptive behavior disorders,impulse control disorders, borderline personality disorder, obsessivecompulsive disorder, chronic fatigue syndrome, premature ejaculation,erectile difficulty, anorexia nervosa, disorders of sleep, autism,mutism, trichotillomania, trigeminal neuralgia, dental pain ortemperomandibular joint dysfunction pain. The compounds of thisinvention are also useful as a prophylactic treatment for migraine. Anyof these methods employ a compound of Formula I.

The use of a compound of Formula I for the activation of the 5-HT_(1F)receptor, for the inhibition of peptide extravasation in general or dueto stimulation of the trigeminal ganglia specifically, and for thetreatment of any of the disorders described supra, are all embodimentsof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The general chemical terms used in the formulae above have their usualmeanings For example, the terms "alkyl, alkoxy and alkylthio" includesuch groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, 2-pentyl-, 3-pentyl-, neopentyl, hexyl,heptyl, octyl and the like. The term "alkenyl" includes vinyl, allyl,1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl,1-hexen-6-yl, 2-hexen-6-yl, 3-hexen-6-yl, 4-hexen-6-yl and the like. Theterm "alkynyl" includes acetylenyl, propynyl, 2-butyn-4-yl,1-butyn-4-yl, 1-pentyn-5-yl, 2-pentyn-5-yl and the like. The term "acyl"includes, for example, formyl, acetyl, propanoyl, butanoyl, and2-methylpropanoyl. The term "cycloalkyl" includes such groups ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. The term "phenyl(C₁ -C₄ alkylene)" includes such groups asbenzyl, phenethyl, phenpropyl and phenbutyl. The term "(C₁ -C₄alkyl)sulfonyl" includes methanesulfonyl, ethanesulfonylpropanesulfonyl, isopropanesulfonyl, butanesulfonyl and the like. Theterm "halo" includes fluoro, chloro, bromo and iodo.

The term "substituted phenyl" or "phenyl(C₁ -C₄ alkylene) substituted inthe phenyl ring" is taken to mean the phenyl moiety may be substitutedwith one substituent selected from the group consisting of halo, C₁ -C₄alkyl, C₁ -C₈ alkoxy, C₁ -C₄ alkylthio, nitro, cyano, di(C₁ -C₄alkyl)amino, trifluoromethyl, trifluoromethoxy, phenyl, C₁ -C₄ acyl,benzoyl or (C₁ -C₄ alkyl)sulfonyl, or two to three substituentsindependently selected from the group consisting of halo, nitro, C₁ -C₄alkyl, or C₁ -C₄ alkoxy.

The term "heterocycle" is taken to mean stable aromatic and non-aromatic5- and 6-membered rings containing from 1 to 3 heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur, said rings beingoptionally benzofused. All of these rings may be substituted with up tothree substituents independently selected from the group consisting ofhalo, C₁ -C₄ alkoxy, C₁ -C₄ alkyl, cyano, nitro, hydroxy, --S(O)_(n)--(C₁ -C₄ alkyl) and --S(O)_(n) --phenyl where n is 0, 1 or 2.Non-aromatic rings include, for example, pyrrolidinyl, piperidinyl,piperazinyl, tetrahydrofuryl, oxazolidinyl, dioxanyl, pyranyl, and thelike. Benzofused non-aromatic rings include indolinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and thelike. Aromatic rings include furyl, thienyl, pyridinyl, pyrrolyl,N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl,pyridazinyl, and the like. Benzofused aromatic rings includeisoquinolinyl, benzoxazolyl, benzthiazolyl, quinolinyl, benzofuranyl,thionaphthyl, indolyl and the like.

The term "heteroaryl" is taken to mean an aromatic or benzofusedaromatic heterocycle as defined in the previous paragraph. The term"substituted heteroaryl" is taken to mean an aromatic or benzofusedaromatic heterocycle as defined in the previous paragraph substitutedwith up to three substituents independently selected from the groupconsisting of halo, C₁ -C₄ alkoxy, C₁ -C₄ alkyl, cyano, nitro, hydroxy,--S(O)_(n) --(C₁ -C₄ alkyl) and --S(O)_(n) --phenyl where n is 0, 1 or2. The term "heteroaryl(C₁ -C₄ alkyl) is taken to mean a branched orlinear alkyl chain of 1 to 4 carbon atoms substituted at some point withan aromatic or benzofused aromatic heterocycle moiety. The term"substituted heteroaryl(C₁ -C₄ alkyl)" is taken to mean a branched orlinear alkyl chain of 1 to 4 carbon atoms substituted at some point withan aromatic or benzofused aromatic heterocycle moiety which issubstituted with up to three substituents independently selected fromthe group consisting of halo, C₁ -C₄ alkoxy, C₁ -C₄ alkyl, cyano, nitro,hydroxy, --S(O)_(n) --(C₁ -C₄ alkyl) and --S(O)_(n) --phenyl where n is0, 1 or 2.

The term "heteroaryloxy" is taken to mean a heteroaryl or substitutedheteroaryl group, as defined in the previous paragraph, bonded to anoxygen atom.

The term "aryloxy" is taken to mean a phenyl or substituted phenyl groupbonded to an oxygen atom.

The term "4-substituted piperazine" is taken to mean a piperazine ringsubstituted at the 4-position with a substituent selected from the groupconsisting of C₁ -C₆ alkyl, C₁ -C₄ alkoxy substituted C₁ -C₆ alkyl,phenyl, substituted phenyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄alkylene) substituted in the phenyl ring, heteroaryl, and heteroaryl(C₁-C₄ alkylene).

The term "substituted piperidine" is taken to mean a piperidine ringoptionally substituted with a substituent selected from the groupconsisting of hydroxy, hydroxymethyl, and N,N-di(C₁ -C₄alkyl)carboxamido.

The term "benzofused C₄ -C₈ cycloalkyl" is taken to mean a C₄ -C₈cycloalkyl group fused to a phenyl ring. Examples of these groupsinclude benzocyclobutyl, indanyl, 1,2,3,4-tetrahydronaphthyl, and thelike.

While all of the compounds of this invention are useful as 5-HT_(1F)agonists, certain classes are preferred. The following paragraphsdescribe such preferred classes.

aa) A--B is --C═CH--;

ab) A--B is --CH--CH₂ --;

ac) R is H;

ad) R is C₁ -C₄ alkyl;

ae) R is methyl;

af) R¹ is methyl;

ag) R¹ is H;

ah) X is --S--R² ;

ai) X is --C(O)R³ ;

aj) X is --C(O)NR⁴ R¹⁵ ;

ak) X is --NR⁵ R⁶ ;

al) X is --NR⁷ SO₂ R⁸ ;

am) X is --NHC(Q)NR¹⁰ R¹¹ ;

an) X is --NHC(O)OR¹² ;

ao) X is --NR¹³ C(O)R¹⁴ ;

ap) Q is O;

aq) R² is phenyl monosubstituted with halo;

ar) R² is 4-chlorophenyl;

as) R² is phenyl(C₁ -C₄ alkylene);

at) R² is benzyl;

au) R² is pyridinyl;

av) R² is 2-pyridinyl;

aw) R³ is C₁ -C₄ alkyl;

ax) R³ is methyl;

ay) R³ is butyl;

az) R³ is phenyl(C₁ -C₄ alkylene);

ba) R³ is benzyl;

bb) R³ is phenyl;

bc) R³ is heteroaryl;

bd) R⁴ is heteroaryl or substituted heteroaryl;

be) R⁴ is heteroaryl(C₁ -C₄ alkyl) or substituted heteroaryl(C₁ -C₄alkyl);

bf) R⁷ is C₁ -C₄ alkyl;

bg) R⁷ is methyl;

bh) R⁷ is H;

bi) R⁸ is C₁ -C₄ alkyl;

bj) R⁸ is methyl;

bk) R⁸ is ethyl;

bl) R⁸ is phenyl;

bm) R⁸ is di(C₁ -C₄ alkyl)amino;

bn) R⁸ is dimethylamino;

bo) R¹⁰ is H;

bp) R¹¹ is C₁ -C₄ alkyl;

bq) R¹¹ is methyl;

br) R¹¹ is ethyl;

bs) R¹¹ is propyl;

bt) R¹¹ is isopropyl;

bu) R¹¹ is phenyl;

bv) R¹¹ is C₃ -C₈ alkenyl;

bw) R¹¹ is allyl;

bx) R¹¹ is phenyl monosubstituted with halo;

by) R¹¹ is 4-fluorophenyl;

bz) R¹¹ is 4-chlorophenyl;

ca) R¹¹ is phenyl(C₁ -C₄ alkylene)

cb) R¹¹ is benzyl;

cc) R¹¹ is phenethyl;

cd) R¹⁰ and R¹¹ taken together with nitrogen form a morpholine ring;

ce) R¹⁰ and R¹¹ taken together with nitrogen form a thiomorpholine ring;

cf) R¹⁰ and R¹¹ taken together with nitrogen form a pyrrolidine ring;

cg) R¹⁰ and R¹¹ taken together with nitrogen form a piperidine ring;

ch) R¹⁰ and R¹¹ taken together with nitrogen form a pyrrolidine ring;

ci) R¹⁰ and R¹¹ taken together with nitrogen form a piperazine ring;

cj) R¹⁰ and R¹¹ taken together with nitrogen form a 4-substitutedpiperazine ring;

ck) R¹² is C₁ -C₄ alkyl;

cl) R¹² is methyl;

cm) R¹² is ethyl;

cn) R¹² is propyl;

co) R¹² is C₃ -C₆ alkenyl;

cp) R¹² is allyl;

cq) R¹² is C₃ -C₈ cycloalkyl;

cr) R¹² is cyclopentyl;

cs) R¹² is phenyl monosubstituted with C₁ -C₄ alkoxy;

ct) R¹² is 4-methoxyphenyl;

cu) R¹³ is H;

cv) R¹³ is C₁ -C₄ alkyl;

cw) R¹⁴ is C₃ -C₆ alkenyl;

cx) R¹⁴ is allyl;

cy) R¹⁴ is C₃ -C₆ cycloalkyl;

cz) R¹⁴ is cyclopropyl;

da) R¹⁴ is cyclobutyl;

db) R¹⁴ is phenyl(C₁ -C₄ alkylene);

dc) R¹⁴ is C₁ -C₄ alkyl ω-substituted with phenoxy;

dd) R¹⁴ is C₁ -C₄ alkyl ω-substituted with C₁ -C₄ alkoxy;

de) R¹⁴ is methoxymethyl;

df) R¹⁴ is ethoxymethyl;

dg) R¹⁴ is phenyl;

dh) R¹⁴ is 2-phenylethylen-1-yl;

di) R¹⁴ is phenyl monosubstituted with halo;

dj) R¹⁴ is phenyl monosubstituted with chloro;

dk) R¹⁴ is phenyl monosubstituted with fluoro;

dl) R¹⁴ is 4-fluorophenyl;

dm) R¹⁴ is 2-chlorophenyl;

dn) R¹⁴ is phenyl monosubstituted with C₁ -C₄ alkoxy;

do) R¹⁴ is phenyl monosubstituted with methoxy;

dp) R¹⁴ is 4-methoxyphenyl;

dq) R¹⁴ is phenyl monosubstituted with C₁ -C₄ alkyl;

dr) R¹⁴ is phenyl monosubstituted with methyl;

ds) R¹⁴ is phenyl monosubstituted with trifluoromethyl, C₁ -C₄alkylthio, cyano, nitro, phenyl, C₁ -C₄ acyl or benzoyl;

dt) R¹⁴ is 4-cyanophenyl;

du) R¹⁴ is 4-nitrophenyl;

dv) R¹⁴ is 4-phenylphenyl;

dw) R¹⁴ is phenyl disubstituted with substitutents selected from halo,C₁ -C₄ alkyl, C₁ -C₄ alkoxy and nitro;

dx) R¹⁴ is phenyl disubstituted with halo;

dy) R¹⁴ is 2,4-dichlorophenyl;

dz) R¹⁴ is a heterocycle;

ea) R¹⁴ is furyl optionally substituted with C₁ -C₄ alkyl, C₁ -C₄alkoxy, or halo;

eb) R¹⁴ is 2-furyl;

ec) R¹⁴ is 3-furyl;

ed) R¹⁴ is thienyl optionally substituted with halo, C₁ -C₄ alkyl or C₁-C₄ alkoxy;

ef) R¹⁴ is 2-thienyl;

eg) R¹⁴ is 3-thienyl;

eh) R¹⁴ is 3-methyl-2-thienyl;

ei) R¹⁴ is 5-methyl-2-thienyl;

ej) R¹⁴ is pyridinyl optionally substituted with halo, C₁ -C₄ alkyl orC₁ -C₄ alkoxy;

ek) R¹⁴ is 3-pyridinyl;

el) R¹⁴ is 4-pyridinyl;

em) R¹⁴ is 6-halo-3-pyridinyl;

en) R¹⁴ is pyrazinyl;

eo) R¹⁴ is isoxazolyl;

ep) R¹⁴ is 2-benzofuranyl;

eq) R¹⁵ is hydrogen;

er) R¹⁵ is C₁ -C₆ alkyl;

es) R¹⁵ is methyl;

et) R¹⁵ is butyl;

eu) R¹⁵ is isopropyl;

ev) R⁴ and R¹⁵ taken together with the nitrogen atom form a pyrrolidinering;

ew) R⁴ and R¹⁵ taken together with the nitrogen atom form a piperidinering;

ex) R⁴ and R¹⁵ taken together with the nitrogen atom form a substitutedpiperidine ring;

ey) R⁴ and R¹⁵ taken together with the nitrogen atom form a piperazinering;

ez) R⁴ and R¹⁵ taken together with the nitrogen atom form a4-substituted piperazine ring;

fa) R⁴ and R¹⁵ taken together with the nitrogen atom form a morpholinering;

fb) R⁴ and R¹⁵ taken together with the nitrogen atom form athiomorpholine ring;

fc) The compound is a free base;

fd) The compound is a salt;

fe) The compound is the hydrochloride salt;

ff) The compound is the fumarate salt;

fg) The compound is the oxalate salt.

It will be understood that the above classes may be combined to formadditional preferred classes.

The compounds of this invention are useful in a method for increasingactivation of the 5-HT_(1F) receptor for treating a variety of disorderswhich have been linked to decreased neurotransmission of serotonin inmammals. It is preferred that the mammal to be treated by theadministration of compounds of this invention is human.

Since the compounds of this invention are amines, they are basic innature and accordingly react with any of a number of inorganic andorganic acids to form pharmaceutically acceptable acid addition salts.Since some of the free amines of the compounds of this invention aretypically oils at room temperature, it is preferable to convert the freeamines to their pharmaceutically acceptable acid addition salts for easeof handling and administration, since the latter are routinely solid atroom temperature. Acids commonly employed to form such salts areinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, phosphoric acid, and the like, and organic acids,such as p-toluene-sulfonic acid, methanesulfonic acid, oxalic acid,p-bromo-phenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propion-ate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,suc-cinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methyl-benzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, b-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid, oxalic acid or fumaric acid.

The following group is illustrative of compounds contemplated within thescope of this invention:

5-(4-fluorophenyl)thio-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-chlorophenyl)thio-3-(1-(pent-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-1H-indole

5-(2-bromophenyl)thio-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-iodophenyl)thio-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-methoxyphenyl)thio-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-iodophenyl)thio-3-(1-(pent-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-ethoxyphenyl)thio-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-ethoxyphenyl)thio-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-propoxyphenyl)thio-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolehydrochloride

5-(2-isopropoxyphenyl)thio-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-isopropoxyphenyl)thio-3-(1-(isobutyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolehydrobromide

5-(3-butoxyphenyl)thio-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolehydrolodide

5-(2-isobutoxyphenyl)thio-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-isobutoxyphenyl)thio-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoleacetate

5-(3-sec-butoxyphenyl)thio-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-tert-butoxyphenyl)thio-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolepropionate

5-(4-tert-butoxyphenyl)thio-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-pyridinyl)thio-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoledecanoate

5-(4-pyridinyl)thio-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-phenethyl)thio-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolecaprylate

5-(4-phenbutyl)thio-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorophenyl)thio-3-(1-(neopentyl)piperidin-4-yl)-1H-indoleacrylate

5-(4-bromophenyl)thio-3-(1-(pent-3-yl)piperidin-4-yl)-1H-indole

5-(2-bromophenyl)thio-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole formate

5-(3-iodophenyl)thio-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(2-methoxyphenyl)thio-3-(1-butylpiperidin-4-yl)-1H-indole isobutyrate

5-(4-methoxyphenyl)thio-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(3-ethoxyphenyl)thio-3-(1-isobutylpiperidin-4-yl)-2-methyl-1H-indolecaproate

5-(2-propoxyphenyl)thio-3-(1-propylpiperidin-4-yl)-1H-indole

5-(4-propoxyphenyl)thio-3-(1-(sec-butyl)piperidin-4-yl)-1H-indoleheptanoate

5-(3-isopropoxyphenyl)thio-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(2-butoxyphenyl)thio-3-(1-propylpiperidin-4-yl)-1H-indole propiolate

5-(4-butoxyphenyl)thio-3-(piperidin-4-yl)-1H-indole

5-(2-sec-butoxyphenyl)thio-3-(1-propylpiperidin-4-yl)-1H-indole oxalate

5-(4-sec-butoxyphenyl)thio-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(2-tert-butoxyphenyl)thio-3-(1-isopropylpiperidin-4-yl)-1H-indolemalonate

5-(3-pyridinyl)thio-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-benzylthio-3-(1-butylpiperidin-4-yl)-1H-indole succinate

5-(3-phenpropyl)thio-3-(1-propylpiperidin-4-yl)-1H-indole

5-propanoyl-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolesuberate

5-(2-methylpropanoyl)-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-butanoyl-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolesebacate

5-(sec-butanoyl)-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-methylbutanoyl)-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-1H-indolefumarate

5-(3,3-dimethylbutanoyl)-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-heptanoyl-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolebutyne-1,4-dioate

5-(3-chlorobenzoyl)-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-fluorobenzoyl)-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-bromobenzoyl)-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolehydrobromide

5-(2-bromobenzoyl)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-iodobenzoyl)-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-methoxybenzoyl)-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-ethoxybenzoyl)-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-ethoxybenzoyl)-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-propoxybenzoyl)-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolehydrochloride

5-(3-propoxybenzoyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-butoxybenzoyl)-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-methylbenzoyl)-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-ethylbenzoyl)-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-propylbenzoyl)-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-propylbenzoyl)-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-butylbenzoyl)-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-trifluoromethylbenzoyl)-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-trifluoromethoxybenzoyl)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-dimethylaminobenzoyl)-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-phenylpropanoyl)-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(5-phenylpentanoyl)-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-pyridinecarbonyl)-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-phenylpropanoyl)-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-butanoyl-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(3-methyl)butanoyl-3-(1-butylpiperidin-4-yl)-2-methyl-1H-indole

5-(2,2-dimethyl)propanoyl-3-(1-(2-pentyl)piperidin-4-yl)-1H-indolefumarate

5-hexanoyl-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(2-ethyl)butanoyl-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)-3-(piperidin-4-yl)-1H-indole

5-(2-fluorobenzoyl)-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(2-bromobenzoyl)-3-(1-propylpiperidin-4-yl)-1H-indole

5-(2-iodobenzoyl)-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(4-iodobenzoyl)-3-(1-(sec-butyl)piperidin-4-yl) -1H-indole

5-(2-methoxybenzoyl)-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(3-ethoxybenzoyl)-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(4-propoxybenzoyl)-3-(1-butylpiperidin-4-yl)-1H-indole

5-(2-butoxybenzoyl)-3-(1-isobutylpiperidin-4-yl)-1H-indolehexyne-1,6-dioate

5-(4-butoxybenzoyl)-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(3-methylbenzoyl)-3-(1-butylpiperidin-4-yl)-1H-indole

5-(4-ethylbenzoyl)-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(2-ethylbenzoyl)-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole benzoate

5-(3-propylbenzoyl)-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(2-butylbenzoyl)-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(4-butylbenzoyl)-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(2-trifluoromethylbenzoyl)-3-(1-butylpiperidin-4-yl)-1H-indolechlorobenzoate

5-(3-trifluoromethoxybenzoyl)-3-(1-propylpiperidin-4-yl)-1H-indole

5-(2-dimethylaminobenzoyl)-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(4-phenylbutanoyl)-3-(1-pentylpiperidin-4-yl)-1H-indole4-methylbenzoate

5-(1-naphthoyl)-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(4-pyridinecarbonyl)-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(N-phenyl)carboxamido-3-(1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-1H-indole2,4-dinitrobenzoate

5-(N-benzyl)carboxamido-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-(2-(4-chlorophenyl)ethyl))carboxamido-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole4-hydroxybenzoate

5-(N-(2-(3-methylphenyl)ethyl))carboxamido-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-(3-(2-methoxyphenyl)propyl))carboxamido-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-(4-(4-trifluoromethylphenyl)butyl))carboxamido-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole3-methoxybenzoate

5-(N-(4-chlorophenyl))carboxamido-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(N-benzyl)carboxamido-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(N-(2-phenethyl))carboxamido-3-(1-(sec-butyl)piperidin-4-yl)-2-methyl-1H-indole

5-(N-(3-phenpropyl))carboxamido-3-(piperidin-4-yl)-1H-indole

5-(N-(3-phenpropyl))carboxamido-3-(1-hexylpiperidin-4-yl)-1H-indolephthalate

5-(N-(4-phenbutyl))carboxamido-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(N-methyl-N-ethanesulfonyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-ethyl-N-propanesulfonyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-isopropanesulfonyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-propyl-N-butanesulfonyl)amino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-isobutanesulfonyl)amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolemethanesulfonate

5-(N-sec-butanesulfonyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-tert-butanesulfonyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-butyl-N-benzenesulfonyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N,N-diethylaminosulfonyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-1H-indole

5-(N,N-dipropylaminosulfonyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N,N-diisopropylaminosulfonyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N,N-dibutylaminosulfonyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(N-ethanesulfonyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indolephenylsulfonate

5-(N-propanesulfonyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(N-isopropanesulfonyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(N-butanesulfonyl)amino-3-(piperidin-4-yl)-1H-indole

5-(N-isobutanesulfonyl)amino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(N-isopropyl-N-sec-butanesulfonyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(N-(tert-butyl)sulfonyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(N,N-diethylaminosulfonyl)amino-3-(1-isobutyl-piperidin-4-yl)-1H-indole

5-(N,N-dipropylaminosulfonyl)amino-3-(1-ethyl-piperidin-4-yl)-2-methyl-1H-indole

5-(N,N-diisopropylaminosulfonyl)amino-3-(1-(2-pentyl)-piperidin-4-yl)-1H-indole

5-(N,N-dibutylaminosulfonyl)amino-3-(1-hexylpiperidin-4-yl)-1H-indole

N-ethyl-N'-(3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-isopropyl-N'-(3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(3-methoxy)phenyl-N'-(3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(2-ethoxy)phenyl-N'-(2-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(2-ethoxy)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(3-ethoxy)phenyl-N'-(3-(1-(2-hexyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(3-propoxy)phenyl-N'-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(3-isopropoxy)phenyl-N'-(3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(4-isopropoxy)phenyl-N'-(3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thioureaphenylacetate

N-(3-butoxy)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thioureahydrochloride

N-(2,3-dibromo)phenyl-N'-(3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(2-bromo-3-iodo)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(3,4-difluoro)phenyl-N'-(3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(3-chloro-4-bromo)phenyl-N'-(3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(2-bromo-4-fluoro)phenyl-N'-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(2,4-diiodo)phenyl-N'-(3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(2-chloro-5-iodo)phenyl-N'-(3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(2-fluoro-6-iodo)phenyl-N'-(3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(3-fluoro-5-chloro)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-phenethyl-N'-(3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(4-phenbutyl)-N'-(3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(2-trifluoromethyl)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-(3-phenyl)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiourea

N-propyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-butyl-N'-(3-(1-isopropylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2-methoxy)phenyl-N'-(3-(1-(sec-butyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(4-ethoxy)phenyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(4-propoxy)phenyl-N'-(2-methyl-3-(1-ethylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-(²-propoxy)phenyl-N'-(3-(1-(tert-butyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2-isopropoxy)phenyl-N'-(3-(1-isobutylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-(4-butoxy)phenyl-N'-(3-piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2-butoxy)phenyl-N'-(3-(1-hexylpiperidin-4-yl)-1H-indol-5-yl) thioureafumarate

N-(2-methoxy)phenyl-N'-(3-(1-(ec-butyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2,3-dibromo)phenyl-N'-(3-(1-isopropylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2-bromo-3-iodo)phenyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(3,4-difluoro)phenyl-N'-(3-(1-butylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-(3-chloro-4-bromo)phenyl-N'-(3-(1-(3-pentyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2-bromo-4-fluoro)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2,4-diiodo)phenyl-N'-(3-(1-(sec-butyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2-chloro-5-iodo)phenyl-N'-(3-(1-hexylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-(2-fluoro-6-iodo)phenyl-N'-(3-(1-(tert-butyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(3-fluoro-5-chloro)phenyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(3-phenpropyl)-N'-(3-(1-(s-butyl)piperidin-4-yl)-1H-indol-5-yl)thiourea

N-(4-trifluoromethyl)phenyl-N'-(3-(1-neopentylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-(4-phenyl)phenyl-N'-(3-(1-pentylpiperidin-4-yl)-1H-indol-5-yl)thiourea

N-pentyl-N'-(3-(1-ethyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(1-buten-4-yl)-N'-(3-(1-isopropyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(1-penten-5-yl)-N'-(3-(1-isobutyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)ureahydrochloride

N-(3-penten-5-yl)-N'-(3-(1-(tert-butyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-hexen-6-yl)-N'-(3-(1-(2-pentyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-hexen-6-yl)-N'-(3-(1-neopentyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-cyclobutyl-N'-(3-(1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-cycloheptyl-N'-(3-(1-pentyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-chloro)phenyl-N'-(2-methyl-3-(1-propyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-bromo)phenyl-N'-(3-(1-(sec-butyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-bromo)phenyl-N'-(3-(1-(3-pentyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-fluoro)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-iodo)phenyl-N'-(3-(1-ethyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-iodo)phenyl-N'-(3-(1-(tert-butyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-methoxy)phenyl-N'-(3-(1-butyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-ethoxy)phenyl-N'-(3-(1-pentyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-propoxy)phenyl-N'-(3-(1-(tert-butyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-propoxy)phenyl-N'-(3-(1-hexyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-isopropoxy)phenyl-N'-(3-(1-isopropyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-butoxy)phenyl-N'-(3-(1-methyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-butoxy)phenyl-N'-(3-(1-butyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-formyl)phenyl-N'-(3-(1-pentyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-acetyl)phenyl-N'-(3-(1-hexyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-propanoyl)phenyl-N'-(3-(1-isobutyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-propanoyl)phenyl-N'-(3-(1-neopentyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-methylthio)phenyl-N'-(3-(1-butyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-ethylthio)phenyl-N'-(3-(1-pentyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-propylthio)phenyl-N'-(3-(1-(tert-butyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)ureafumarate

N-(4-propylthio)phenyl-N'-(3-(1-hexyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-butylthio)phenyl-N'-(3-(1-ethyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-butylthio)phenyl-N'-(3-(1-isobutyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-methyl)phenyl-N'-(3-(1-propyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-ethyl)phenyl-N'-(3-(1-(sec-butyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-ethyl)phenyl-N'-(3-(1-(3-pentyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-propyl)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-isopropyl)phenyl-N'-(3-(1-ethyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-butyl)phenyl-N'-(3-(1-propyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-methoxycarbonyl)phenyl-N'-(3-(1-(sec-butyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-ethoxycarbonyl)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-propoxycarbonyl)phenyl-N'-(3-(1-ethyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-propoxycarbonyl)phenyl-N'-(3-(1-isobutyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-butoxycarbonyl)phenyl-N'-(3-(1-neopentyl-1,2,3,4-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2,3-dibromo)phenyl-N'-(3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-bromo-3-iodo)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3,4-difluoro)phenyl-N'-(3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-chloro-4-bromo)phenyl-N'-(3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-bromo-4-fluoro)phenyl-N'-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2,4-diiodo)phenyl-N'-(3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-chloro-5-iodo)phenyl-N'-(3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(2-fluoro-6-iodo)phenyl-N'-(3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(3-fluoro-5-chloro)phenyl-N'-(3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-(4-phenbutyl)-N'-(3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-phenyl-N-propyl-N'-(3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-phenyl-N-butyl-N'-(3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-methyl-N-propyl-N'-(3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-ethyl-N-isopropyl-N'-(3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N,N-dipropyl-N'-(3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-butyl-N-propyl-N'-(3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-butyl-N-isopropyl-N'-(3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)urea

N-hexyl-N'-(3-(1-propylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-buten-4-yl)-N'-(3-(1-butylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-penten-5-yl)-N'-(3-(1-(sec-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(1-hexen-6-yl)-N'-(3-(1-pentylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-hexen-6-yl)-N'-(3-(1-(3-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-cyclopropyl-N'-(3-(1-hexylpiperidin-4-yl)-1H-indol-5-yl)urea

N-cyclopentyl-N'-(3-(1-(3-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-cyclooctyl-N'-(3-(1-(tert-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(2-chloro)phenyl-N'-(3-(1-butylpiperidin-4-yi)-1H-indol-5-yl)urea

N-(3-bromo)phenyl-N'-(3-(1-pentylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-fluoro)phenyl-N'-(3-(1-hexylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-iodo)phenyl-N'-(2-methyl-3-(1-butylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-phenyl)phenyl-N'-(3-(1-propylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(4-ethoxy)phenyl-N'-(3-(1-(sec-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(2-ethoxy)phenyl-N'-(3-(1-neopentylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-propoxy)phenyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(2-isopropoxy)phenyl-N'-(3-(1-ethylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(4-isopropoxy)phenyl-N'-(3-(1-isobutylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-butoxy)phenyl-N'-(3-(1-propylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(4-formyl)phenyl-N'-(3-(1-(sec-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(2-formyl)phenyl-N'-(3-(1-(3-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(3-acetyl)phenyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)ureaphenylpropionate

N-(3-propanoyl)phenyl-N'-(3-(1-pentylpiperidin-4-yl)-1-H-indol-5-yl)urea

N-(3-ethylthio)phenyl-N'-(3-(1-propylpiperidin-4-yl)-1-H-indol-5-yl)urea

N-(2-ethylthio)phenyl-N'-(3-(1-(3-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(3-propylthio)phenyl-N'-(3-piperidin-4-yl)-1H-indol-5-yl)urea

N-(3-isopropylthio)phenyl-N'-(3-(1-isopropylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-methyl)phenyl-N'-(3-(1-propylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-ethyl)phenyl-N'-(3-(1-pentylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-propyl)phenyl-N'-(3-(1-(tert-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(3-isopropyl)phenyl-N'-(3-(1-isopropylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(4-butyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-butyl)phenyl-N'-(3-(1-butylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-methoxycarbonyl)phenyl-N'-(3-(1-pentylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-ethoxycarbonyl)phenyl-N'-(3-(1-(tert-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(4-ethoxycarbonyl)phenyl-N'-(3-(1-hexylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-propoxycarbonyl)phenyl-N'-(3-(1-isobutylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-butoxycarbonyl)phenyl-N'-(3-(1-propylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2,3-dibromo)phenyl-N'-(3-(1-isopropylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-bromo-3-iodo)phenyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(3,4-difluoro)phenyl-N'-(3-(1-butylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(3-chloro-4-bromo)phenyl-N'-(3-(1-(3-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(2-bromo-4-fluoro)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2,4-diiodo)phenyl-N'-(3-(1-(sec-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(2-chloro-5-iodo)phenyl-N'-(3-(1-hexylpiperidin-4-yl)-1H-indol-5-yl)urea

N-(2-fluoro-6-iodo)phenyl-N'-(3-(1-(tert-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(3-fluoro-5-chloro)phenyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-(3-phenpropyl)-N'-(3-(1-propylpiperidin-4-yl)-1H-indol-5-yl)urea

N-ethyl-N-phenyl-N'-(3-(1-butylpiperidin-4-yl)-1H-indol-5-yl)urea

N-isopropyl-N-phenyl-N'-(3-(1-(sec-butyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-ethyl-N-methyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)-1H-indol-5-yl)urea

N-methyl-N-isopropyl-N'-(3-(1-neopentylpiperidin-4-yl)-1H-indol-5-yl)urea

N-ethyl-N-propyl-N'-(3-(1-neopentylpiperidin-4-yl)-1H-indol-5-yl)urea

N-ethyl-N-butyl-N'-(3-(1-(2-pentylpiperidin-4-yl)-1H-indol-5-yl)urea

N-propyl-N-isopropyl-N'-(3-(1-isobutylpiperidin-4-yl)-1H-indol-5-yl)urea

N,N-diisopropyl-N'-(3-(1-butylpiperidin-4-yl)-1H-indol-5-yl)urea

N,N-dibutyl-N'-(3-(1-butylpiperidin-4-yl)-1H-indol-5-yl)urea

5-isopropoxycarbonylamino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-ethyl-1H-indole

5-(1-buten-4-yloxy)carbonylamino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolehydrochloride

5-(1-penten-5-yloxy)carbonylamino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(1-buten-4-yloxy)carbonylamino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-penten-5-yloxy)carbonylamino-3-(1-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-hexen-6-yloxy)carbonylamino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-hexen-6-yloxy)carbonylamino-3-(1-(neopentyl)-

1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorophenoxy)carbonylamino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-fluorophenoxy)carbonylamino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-bromophenoxy)carbonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-bromophenoxy)carbonylamino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-iodophenoxy)carbonylamino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-methoxyphenoxy)carbonylamino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-ethoxyphenoxy)carbonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-ethoxy)phenoxycarbonylamino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-propoxyphenoxy)carbonylamino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-butoxyphenoxy)carbonylamino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-butoxyphenoxy)carbonylamino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-cyclobutoxycarbonylamino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-cyclooctyloxycarbonylamino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(butoxymethoxy)carbonylamino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(ethoxypropoxy)carbonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-butoxycarbonylamino-3-(1-propylpiperidin-4-yl)-2-propyl-1H-indole

5-(2-buten-4-yloxy)carbonylamino-3-(piperidin-4-yl)-1H-indole

5-(2-penten-5-yloxy)carbonylamino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(1-hexen-6-yloxy)carbonylamino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(3-hexen-6-yloxy)carbonylamino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(3-chlorophenoxy)carbonylamino-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(2-fluorophenoxy)carbonylamino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(4-fluorophenoxy)carbonylamino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(4-bromophenoxy)carbonylamino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(2-iodophenoxy)carbonylamino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(4-iodophenoxy)carbonylamino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(3-chlorophenoxy)carbonylamino-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(2-methoxyphenoxy)carbonylamino-3-(1-hexylpiperidin-4-yl)-2-ethyl-1H-indolecitrate

5-(3-ethoxyphenoxy)carbonylamino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(4-propoxyphenoxy)carbonylamino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(2-propoxyphenoxy)carbonylamino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(3-butoxyphenoxy)carbonylamino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-cyclopropoxycarbonylamino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-cyclohexyloxycarbonylamino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-cyclooctyloxycarbonylamino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(propoxyethoxy)carbonylamino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(4-methoxybutoxy)carbonylamino(1-ethylpiperidin-4-yl)-1H-indole

5-(acetyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(butyroyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(pentanoyl)amino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoleglycollate

5-(2-methylbutanoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2,2-dimethylpropanoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(heptanoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(cyclooctylcarbonyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-phenylbutanoyl)amino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(phenoxyacetyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-phenoxybutanoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(butoxyacetyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-ethoxybutanoyl)amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoletartrate

5-(butoxycarbonylacetyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-butoxycarbonylbutanoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolehydrochloride

5-benzoylamino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-benzoylamino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolepropanesulfonate

5-benzoylamino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolefumarate

5-(4-fluorobenzoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)-N-methylamino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolenaphthalene-1-sulfonate

5-(4-fluorobenzoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)-N-ethylamino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-bromobenzoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-iodobenzoyl)-N-propylamino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-ethylbenzoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-propylbenzoyl)amino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-propylbenzoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-butylbenzoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-ethoxybenzoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-ethoxybenzoyl)-N-isopropylamino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-propoxybenzoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-butoxybenzoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-butoxybenzoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-pentoxybenzoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-hexyloxybenzoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-heptyloxybenzoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-octyloxybenzoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-octyloxybenzoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-octyloxybenzoyl)amino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-methylthiobenzoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-propylthiobenzoyl)-N-butylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-propylthiobenzoyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-butylthiobenzoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-nitrobenzoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-cyanobenzoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-(dimethylamino)benzoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-(diethylamino)benzoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-(dipropylamino)benzoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-trifluoromethoxybenzoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-trifluoromethoxybenzoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-formylbenzoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-acetylbenzoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-(propanoyl)benzoyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(4-(propanoyl)benzoyl)amino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-(butanoyl)benzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-(benzoyl)benzoyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-methanesulfonylbenzoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-ethanesulfonylbenzoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-butanesulfonylbenzoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-butanesulfonylbenzoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-phenylbenzoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2,3-dibromo)benzoylamino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-bromo-3-iodo)benzoylamino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3,4-difluoro)benzoylamino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-chloro-4-bromo)benzoylamino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-bromo-4-fluoro)benzoylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2,4-diiodo)benzoylamino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-chloro-5-iodo)benzoylamino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-fluoro-6-iodo)benzoylamino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-fluoro-5-chloro)benzoylamino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yi)-1H-indole

5-(2-furoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-(sec-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-(tert-butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-(2-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolenaphthalene-2-sulfonate

5-(3-furoyl)amino-3-(1-(3-pentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-neopentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-hexyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

5-(propanoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole mandalate

5-(2-methylpropanoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(2-methyl-4-butyn-1-oyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(2-methylbutanoyl)-N-methylamino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(hex-3-enoyl)amino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(cyclohexaneacetyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(cycloheptylcarbonyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(4-phenylbutanoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(5-phenylpentanoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(3-phenoxypropanoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(5-phenoxypentanoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(3-propoxypropanoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(5-methoxypentanoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-((3-propoxycarbonyl)propanoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-((5-methoxycarbonyl)pentanoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(benzoyl-N-ethyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-propylpiperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-butylpiperidin-4-yl)-1H-indole

5-benzoylamino-3-(piperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole hydrochloride

5-benzoyl-N-propylamino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-benzoylamino-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-isobutylpiperidin-4-yl)-1-H-indole

5-(4-fluorobenzoyl)amino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(4-fluorobenzoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indolefumarate

5-(4-fluorobenzoyl)amino-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H- indole

5-(2-chlorobenzoyl)amino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(2-chlorobenzoyl)amino-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(2-bromobenzoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(4-ethylbenzoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(2-ethylbenzoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(3-propylbenzoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(4-butylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

5-(2-butylbenzoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(3-ethoxybenzoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(2-propoxybenzoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(3-butoxybenzoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(4-pentyloxybenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

5-(2-pentyloxybenzoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(2-hexyloxybenzoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(4-hexyloxybenzoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(2-methylthiobenzoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(2-ethylthiobenzoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(3-propylthiobenzoyl)amino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(3-nitrobenzoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(3-cyanobenzoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(4-(dimethylamino)benzoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(2-(diethylamino)benzoyl)-N-propylamino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(4-(diethylamino)benzoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(3-(dibutylamino)benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

5-(4-trifluoromethoxybenzoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(4-(formyl)benzoyl)amino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(2-(formyl)benzoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(2-(acetyl)benzoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(3-(propanoyl)benzoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(3-(butanoyl)benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

5-(2-(butanoyl)benzoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(2-(benzoyl)benzoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(2-(methanesulfonyl)benzoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(3-(propanesulfonyl)benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

5-(2-butanesulfonylbenzoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(3-phenylbenzoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(2,3-dibromo)benzoyl-N-isopropylamino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(2-bromo-3-iodo)benzoylamino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(3,4-difluoro)benzoylamino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(3-chloro-4-bromo)benzoylamino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(2-bromo-4-fluoro)benzoylamino-(3-(1-methylpiperidin-4-yl)-1H-indole

5-(2,4-diiodo)benzoylamino-(3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(2-chloro-5-iodo)benzoylamino-(3-(1-hexylpiperidin-4-yl)-1H-indole

5-(2-fluoro-6-iodo)benzoylamino-(3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(3-fluoro-5-chloro)benzoylamino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(2-thienoyl)-N-butylamino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(2-thienoyl)amino-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(3-thienoyl)amino-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(2-furoyl)amino-3-(1-hexylpiperidin-4-yl)-1H-indole

5-(³ -furoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-propylpiperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-isopropylpiperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-butylpiperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-isobutylpiperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-(sec-butyl)piperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-pentylpiperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-(2-pentyl)piperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-neopentylpiperidin-4-yl)-1H-indole

5-(3-furoyl)amino-3-(1-hexylpiperidin-4-yl)-1H-indole

N-pyridin-2-yl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

N-fur-3-yl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

N-pyrazol-3-yl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

N-thiazol-2-yl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

N-quinolin-4-yl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

N- imidazol-4-yl!-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole

N-fur-3-yl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

N- pyrimidin-5-yl!-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole

N- indol-2-yl!-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole

N- isoxazol-5-yl!-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole

The compounds of this invention are prepared by methods well known toone of ordinary skill in the art, such as that generally described inU.S. Pat. No. 4,443,451, hereby incorporated by reference. While thesimple indoles required for the preparation of the compounds of thisinvention are generally commercially available, their preparations aredescribed in Robinson, The Fischer Indole Synthesis, Wiley, New York(1983); Hamel, et al., Journal of Organic Chemistry, 59, 6372 (1994);and Russell, et al., Organic Preparations and Procedures International,17, 391 (1985).

The compounds of the invention where X is --NR⁷ SO₂ R⁸ may be preparedby first modifying an appropriate 5-aminoindole. When R⁷ is hydrogen,the 5-aminoindole is reacted with an appropriate sulfonyl halide oranhydride to give the corresponding sulfonamide. When R⁷ is lower alkyl,however, the 5-aminoindole is first acylated, and then reduced with anappropriate hydride reducing agent. Alternatively, the 5-aminoindole maybe reductively alkylated with an appropriate aldehyde or ketone in thepresence of a suitable hydride reducing agent to give the appropriatelysubstituted indole. These substituted indoles are then reacted with asulfonyl halide or anhydride to give the corresponding sulfonamide. Thischemistry is illustrated in Synthetic Scheme I, where M is methoxy,ethoxy, methyl, ethyl, propyl, or isopropyl, LG is chloro or bromo, andR¹, R⁷, and R⁸ are as defined supra. ##STR3##

When R⁷ is to be hydrogen, a solution of 5-aminoindole in a suitablesolvent, such as tetrahydrofuran, dioxane, diethyl ether ordimethylformamide, at a temperature from about ambient to about 0° C.,is reacted with a commercially available R⁸ -sulfonyl halide or R⁸-sulfonic anhydride in the presence of a suitable base such as pyridineor triethylamine. The resultant sulfonamide may be isolated by dilutionof the reaction mixture with water, adjustment of pH, and extractionwith a water immiscible solvent such as dichloromethane. The product maybe used for further reaction as recovered, or may be purified bychromatography, or by recrystallization from a suitable solvent.

When R⁷ is to be lower alkyl, a solution of 5-aminoindole in a suitablesolvent, such as tetrahydrofuran, dioxane, or diethyl ether, at atemperature from about ambient to about 0° C., is reacted with acompound of structure M--C(O)-halo in the presence of a suitable basesuch as pyridine or triethylamine. The resultant compound is isolated bydilution of the reaction mixture with water and extraction with a waterimmiscible solvent such as dichloromethane. This acylated product mayeither be purified chromatographically or used directly in thesubsequent step. The acylated product is then dissolved in a suitablesolvent, such as tetrahydrofuran or diethyl ether, at a temperature fromabout ambient to about 0° C., and is treated with a suitable hydridereducing agent such as diborane or lithium aluminum hydride. Thereaction is stirred from 1 to 24 hours and is then treated with aqueoussolution of sodium sulfate. The resultant suspension is filtered, andthe filtrate concentrated under reduced pressure. The product may beused for further reaction as is, purified by chromatography, orrecrystallized from a suitable solvent.

Alternatively, a solution of a 5-aminoindole in a solvent suitable forthe azeotropic removal of water, such as toluene, benzene orcyclohexane, is reacted at reflux with an appropriate aldehyde orketone, such as formaldehyde, acetaldehyde, propanal, butanal oracetone, in the presence of 0.1-10% of a proton source such asp-toluenesulfonic acid. When the reaction is complete the volatiles areremoved under reduced pressure and the residue redissolved in an alkanolsuch as methanol or ethanol. This solution is then subjected tohydrogenation conditions, or is treated with an appropriate hydridereducing agent, such as sodium borohydride or, preferably, sodiumcyanoborohydride in the presence of an anhydrous acid such as hydrogenchloride. The reaction is then diluted with water, treated with base andextracted into a water immiscible solvent such as dichloromethane. Theproduct may be used as is for further reaction, purified bychromatography or crystallized from a suitable solvent. This product isnow treated with a commercially available R⁸ -sulfonyl halide or R⁸-sulfonic anhydride as described supra to give the requiredsulfonamides.

Compounds of the invention where X is --S--R², --C(O)R³ or --C(O)NR⁴ R¹⁵are prepared by first converting a 5-bromoindole into a5-bromo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or5-bromo-3-(1-piperidin-4-yl)-1H-indole. Compounds of the invention whereX is --NR⁵ R⁶, --NHC(Q)NR¹⁰ R¹¹, --NHC(O)OR¹² or --NR¹³ C(O)R¹⁴ areprepared by first converting a 5-nitro- or 5-aminoindole into a 5-nitro-or 5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or into thecorresponding 5-nitro- or 5-amino-(1-piperidin-4-yl)-1H-indole.Compounds of the invention where X is --NR⁷ SO₂ R⁸ or --NR¹³ C(O)R¹⁴ maybe prepared by converting the appropriately substituted indole into thecorresponding 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or3-(1-piperidin-4-yl)-1H-indole. This chemistry is illustrated inSynthetic Scheme II, where Y is nitro, amino, bromo, --NR¹³ C(O)R¹⁴, or--NR⁷ SO₂ R⁸, and R, R¹, R⁷, R⁸, R¹³ and R¹⁴ are as defined supra.##STR4##

The 5-substituted indole is condensed with a 4-piperidone in thepresence of a suitable base to give the corresponding5-substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. The reactionis performed by first dissolving an excess of the base, typically sodiumor potassium hydroxide, in a lower alkanol, typically methanol orethanol. The indole and two equivalents of the 4-piperidone are thenadded and the reaction refluxed for 8-72 hours. The resulting5-substituted-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indoles may beisolated from the reaction mixture by the addition of water. Compoundswhich precipitate may be isolated directly by filtration while othersmay be extracted by adjusting the pH of the solution and extracting witha water immiscible solvent such as ethyl acetate or dichloromethane. Thecompounds recovered may be used directly in subsequent steps or firstpurified by silica gel chromatography or recrystallization from asuitable solvent.

The5-substituted-3-(1-substituted-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indolesmay be used to prepare other compounds of the invention or, if desired,may be hydrogenated over a precious metal catalyst, such as palladium oncarbon, to give the corresponding5-substituted-3-(piperidin-4-yl)-1H-indoles. When Y is bromo, ahydrogenation catalyst such as sulfided platinum on carbon, platinumoxide, or a mixed catalyst system of sulfided platinum on carbon withplatinum oxide is used to prevent hydrogenolysis of the 5-bromosubstituent during reduction of the tetrahydro-pyridinyl double bond.The hydrogenation solvent may consist of a lower alkanol, such asmethanol or ethanol, tetrahydrofuran, or a mixed solvent system oftetrahydrofuran and ethyl acetate. The hydrogenation may be performed atan initial hydrogen pressure of 20-80 p.s.i., preferably from 50-60p.s.i., at 0-60° C., preferably at ambient temperature to 40° C., for 1hour to 3 days. Additional charges of hydrogen may be required to drivethe reaction to completion depending on the specific substrate. The5-substituted-3-(piperidin-4-yl)-1H-indoles prepared in this manner areisolated by removal of the catalyst by filtration followed byconcentration of the reaction solvent under reduced pressure. Theproduct recovered may be used directly in a subsequent step or furtherpurified by chromatography, or by recrystallization from a suitablesolvent.

As an alternative to hydrogenation, the5-substituted-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indoles may beconverted to the corresponding5-substituted-3-(piperidin-4-yl)-1H-indoles by treatment withtrifluoroacetic acid/triethylsilane if desired. The5-substituted-3-(1-substituted-1,2,5,6-tetrahydro-4-pyridinyl)-1H-indoleis dissolved in trifluoroacetic acid to which is added an excess,1.1-10.0 equivalents, of triethylsilane. The reaction mixture is stirredat about ambient temperature for from about 1 to about 48 hours at whichtime the reaction mixture is concentrated under reduced pressure. Theresidue is then treated with 2N sodium or potassium hydroxide and themixture extracted with a water immiscible solvent such asdichloromethane or diethyl ether. The resultant5-substituted-3-(piperidin-4-yl)-1H-indole is purified by columnchromatography if desired.

The skilled artisan will appreciate that the 5-nitro substituent may bereduced before or after condensation with an appropriate 4-piperidone.Additionally, the nitro group and the 1,2,3,6-tetrahydropyridinyl doublebond may be hydrogenated simultaneously if desired.

The compounds of the invention where X is --S--R² are prepared from thecorresponding 5-bromo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles or5-bromo-3-(piperidin-4-yl)-1H-indoles as illustrated in Synthetic SchemeIII, where A, B, R¹ and R² are as defined supra and R=C₁ -C₄ alkyl.##STR5##

The 5-bromo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles or5-bromo-3-(piperidin-4-yl)-1H-indoles in a suitable aprotic solvent,such as diethyl ether or tetrahydrofuran, are cooled to about 0° C. andtreated with potassium hydride to deprotonate the indole nucleus at the1-position. While other hydrides are useful for this deprotonation, theresultant potassium salt is more soluble in typical reaction solvents.The reaction mixture is then cooled to about -78° C. and halogen-metalexchange effected by the addition of two equivalents of t-butyllithium.To this dianion solution are then added an appropriate disulfide and thereaction mixture allowed to warm to ambient temperature. The compound ofthe invention is isolated by treating the reaction mixture with aqueousbase, such as sodium or potassium hydroxide, and then extracting with awater immisible solvent such as diethyl ether or dichloromethane. Thereaction product may then be purified by column chromatography.

Compounds of the invention where X is --C(O)R³ or --C(O)NR⁴ R¹⁵ areprepared from the corresponding5-bromo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles or5-bromo-3-(piperidin-4-yl)-1H-indoles as illustrated in Synthetic SchemeIV, where A, B, R¹, R³, R⁴ and R¹⁵ are as defined supra and R=C₁ -C₄alkyl. ##STR6##

The dianion of the 5-bromo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolesor 5-bromo-3-(1-substituted-piperidin-4-yl)-1H-indole, prepared asdescribed supra, is then treated with N,N'-dimethyl-N,N'-dimethoxyurea.The resulting N-methyl-N-methoxy-5-carboxamido-1H-indole is isolated bytreating the reaction mixture with aqueous base, such as sodium orpotassium hydroxide, and then extracting with a water immisible solventsuch as diethyl ether or dichloromethane. The reaction product may thenbe purified by column chromatography.

Compounds of the invention where X is --C(O)R³ are prepared by reactinga solution of theN-methyl-N-methoxy-5-carboxamido-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoleor N-methyl-N-methoxy-5-carboxamido-3-(piperidin-4-yl)-1H-indole in asuitable solvent, such as diethyl ether or tetrahydrofuran, at about 0°C., with an appropriate reagent such as an aryl- or alkyllithium or analkyl or aryl Grignard reagent. These reagents are either commerciallyavailable or may be prepared by methods well known to one of ordinaryskill in the art. The aryl- or alkyllithium reagents are convenientlyprepared by treating an appropriate aryl or alkyl halide withn-butyllithium. The aryl or alkyl Grignard reagents may be prepared bytreating an appropriate aryl or alkyl halide with magnesium. Thecompounds of interest may be isolated by aqueous work-up followed byextraction into a water immiscible solvent such as diethyl ether ordichloromethane, and then purified by chromatography, or byrecrystallization from a suitable solvent.

The skilled artisan will also appreciate that the compounds of theinvention where X is --C(O)R³ are also available by the reaction of thedianion of either a 5-bromo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoleor a 5-bromo-3-(piperidin-4-yl)-1H-indole with an appropriate aryl oralkyl N-methyl-N-methoxycarboxamide. These carboxamides are preparedfrom the corresponding carboxylic acids and N-methyl-N-methoxyamineunder standard peptide coupling conditions usingN,N'-dicyclohexylcarbodiimide.

Compounds of the invention where X is --C(O)NR⁴ R¹⁵ are prepared byreacting a solution of theN-methyl-N-methoxy-5-carboxamido-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoleor N-methyl-N-methoxy-5-carboxamido-3-(piperidin-4-yl)-1H-indole in asuitable solvent, such as diethyl ether or tetrahydrofuran, at about 0°C., with the anion of an appropriate amine. These anions are prepared bytreating the appropriate amine with n-butyllithium. The compounds ofinterest may be isolated by aqueous work-up followed by extraction intoa water immiscible solvent such as diethyl ether or dichloromethane, andthen purified by chromatography, or by recrystallization from a suitablesolvent.

Alternatively, compounds of the invention where X is --C(O)NR⁴ R¹⁵ areprepared by subjecting an appropriate indole 5-carboxylic acid and anappropriate amine to standard peptide coupling conditions. The indole5-carboxylic acid in an appropriate solvent may be treated with oxalylchloride, thionyl chloride or phosphorous tribromide in an appropriatesolvent, for example toluene, to prepare the corresponding acid halide.The acid halide in a suitable solvent, for example tetrahydrofuran ordimethylformamide, may be treated with an amine of formula HNR⁴ R¹⁴ inthe presence of a suitable base such as triethylamine, pyridine ordimethylaminopyridine to provide the desired compound. The product maybe isolated by aqueous work-up followed by extraction into a waterimmiscible solvent such as diethyl ether, ethyl acetate ordichloromethane, and then purified by chromatography, or byrecrystallization from a suitable solvent.

Preferably, compounds of the invention where X is --C(O)NR⁴ R¹⁵ areprepared by reacting the appropriate indole 5-carboxylic acid with anappropriate amine in the presence of typical peptide coupling reagentssuch as N,N'-carbonyldiimidazole(CDI), N,N'-dicyclohexylcarbodiimide(DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC).

Compounds of the invention where X is --NR⁵ R⁶, --NHC(Q)NR¹⁰ R¹¹,--NHC(O)OR¹² or --NR¹³ C(O)R¹⁴ are prepared by reacting the appropriate5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or5-amino-3-(piperidin-4-yl)-1H-indole with a suitable electrophile. Thesereactions are illustrated in Synthetic Scheme V, where A, B, R¹, R⁵, R⁶,R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are as described supra and R=C₁ -C₄ alkyl.##STR7##

Compounds of the invention where X is --NR⁵ R⁶ are prepared by treatinga solution of the 5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoleor 5-amino-3-(piperidin-4-yl)-1H-indole in a suitable solvent, such asdichloromethane, tetrahydrofuran, acetonitrile or dimethylformamide,with a suitable electrophile, such as trifluoromethanesulfonic anhydrideor N-carbethoxyphthalimide, in the presence of a suitable base such aspyridine or triethylamine. The reaction product is isolated byevaporation of the reaction solvent under reduced pressure. The productmay be purified by chromatography, or by crystallization from anappropriate solvent.

Compounds of the invention where X is --NHC(Q)NR¹⁰ R¹¹ are prepared bytreating a solution of the5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or5-amino-3-(piperidin-4-yl)-1H-indole in a suitable solvent, such aschloroform or dichloromethane, with an appropriate isocyanate,isothiocyanate, carbamoyl chloride or carbamoyl bromide. Appropriatecarbamoyl chlorides are available by treating an amine of formula HNR¹⁰R¹¹ with phosgene. When a carbamoyl chloride or carbamoyl bromide isused, the reactions are performed in the presence of a suitable base.Suitable bases include amines typically used as acid scavengers, such aspyridine or triethylamine, or commercially available polymer bound basessuch as polyvinylpyridine. If necessary, an excess of the isocyanate,isothiocyanate, carbamoyl chloride or carbamoyl bromide is employed toensure complete reaction of the starting amine. The reactions areperformed at about ambient to about 80° C., for from about three hoursto about three days. Typically, the product may be isolated by washingthe reaction mixture with water and concentrating the remaining organicsunder reduced pressure. When an excess of isocyanate, isothiocyanate,carbamoyl chloride or carbamoyl bromide has been used, however, apolymer bound primary or secondary amine, such as an aminomethylatedpolystyrene, may be conveniently added to react with the excess reagent.Isolation of products from reactions where a polymer bound reagent hasbeen used is greatly simplified, requiring only filtration of thereaction mixture and then concentration of the filtrate under reducedpressure. The product from these reactions may be purifiedchromatographically or recrystallized from a suitable solvent ifdesired. The skilled artisan will appreciate that compounds of theinvention which are ureas may be converted into the correspondingthiourea by treatment with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide!(Lawesson's Reagent) or phosphorus pentasulfide.

Compounds of the invention where X is --NHC(O)OR¹² are prepared byreacting the 5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or5-amino-3-(piperidin-4-yl)-1H-indole with an appropriately substitutedchloroformate in the presence of a suitable amine under the conditionsdescribed in the previous paragraph. Likewise, compounds of theinvention where X is --NR¹³ C(O)R¹⁴ are prepared by reacting the5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or5-amino-3-(piperidin-4-yl)-1H-indole with an appropriate carboxylic acidchloride, bromide or anhydride, optionally in the presence of anacylation catalyst such as dimethylaminopyridine, in the presence of asuitable base, such as those described supra.

Alternatively, compounds of the invention where X is --NR¹³ C(O)R¹⁴ areprepared by reacting the5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or5-amino-3-(piperidin-4-yl)-1H-indole with an appropriate carboxylic acidhalide, carboxylic acid anhydride, or a carboxylic acid in the presenceof typical peptide coupling reagents such as N,N'-carbonyldiimidazole(CDI), N,N'-dicyclohexylcarbodiimide (DCC) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). Apolymer supported form of EDC has been described (Tetrahedron Letters,34(48), 7685 (1993)) and is very useful for the preparation of thecompounds of the present invention. The product from these reactions isisolated and purified as described above.

The skilled artisan will appreciate that the order in which the stepsare performed to prepare the compounds of the present invention is notimportant in many cases. For example, compounds where X is --NR⁷ SO₂ R⁸are accessible by subjecting the5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles or5-amino-3-(piperidin-4-yl)-1H-indoles to the conditions illustrated inSynthetic Scheme I. Likewise, 5-aminoindole may be subjected to thereaction sequences illustrated in Synthetic Scheme V prior to reactionwith a 4-piperidone as illustrated in Synthetic Scheme II. The skilledartisan will also appreciate that compounds where R is H may be preparedby condensing 4-piperidone with a suitably substituted indole to givethe corresponding 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles whichmay then be hydrogenated if desired. Alternatively,1-benzyl-4-piperidone may be substituted at any point in the synthesisfor a suitably substituted 4-piperidone. The benzyl group may then beremoved by standard hydrogenation conditions after reactions for whichthe secondary amine would be incompatible are complete. The3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles may also be reduced to thecorresponding 3-(piperidin-4-yl)-1H-indoles at any convenient point inthe synthetic sequence. These variations are made apparent in thefollowing Preparations and Examples.

PREPARATION I 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole

Preparation of5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

To a solution of 56.11 gm (306 mMol) potassium hydroxide in 300 mLmethanol were added 38 mL (306 mMol) 1-methyl-4-piperidone followed by30.0 gm (153 mMol) 5-bromo-1H-indole. The reaction mixture was stirredat reflux for 18 hours. The reaction mixture was then cooled to ambientand diluted with 1.5 L water. The resultant white solid was filtered,washed sequentially with water and diethyl ether, and then dried undervacuum to give 44.6 gm (100%)5-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole.

Catalytic Hydrogenation

To a solution of 44.6 gm (153 mMol)5-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 1.95 Ltetrahydrofuran were added 9.0 gm platinum oxide. The reaction mixturewas hydrogenated with an initial hydrogen pressure of 60 p.s.i. atambient temperature for 24 hours. The reaction mixture was filtered andthe filtrate concentrated under reduced pressure. The residue wasrecrystallized from acetonitrile to give 32.6 gm (73.7%) of the titlecompound as a white solid.

MS(m/e): 293(M⁺). Calculated for C₁₄ H₁₇ N₂ Br: Theory: C, 57.32; H,5.96; N, 9.69. Found: C, 57.35; H, 5.84; N, 9.55.

PREPARATION IIN-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole

To a suspension of 0.72 gm (3.58 mMol) potassium hydride in 16.0 mLtetrahydrofuran at 0° C. was added a solution of 1.0 gm (3.41 mMol)5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole in 16.0 mL tetrahydrofuranand the solution stirred for about 30 minutes. The resulting mixture wascooled to about -78° C. and to it were added 4.4 mL (7.5 mMol) t-butyllithium, which had been precooled to -78° C., via cannula. After about15 minutes 0.66 gm (3.41 mMol) N,N'-dimethyl-N,N'-dimethoxyurea wereadded and the reaction mixture was allowed to warm gradually to ambient.The reaction mixture was then treated with 5N sodium hydroxide andextracted with diethyl ether. The ether extracts were combined, washedwith saturated aqueous sodium chloride, dried over sodium sulfate andconcentrated under reduced pressure. Purification by flashchromatography, eluting with 4.5:0.5:0.2 ethyl acetate:methanol:toluene,gave 0.61 gm (60%) of the title compound

MS(m/e): 301(M⁺) IR: 1632 cm⁻¹ Calculated for C₁₇ H₂₃ N₃ O₂.0.25 H₂ O:Theory: C, 66.75; H, 7.74; N, 13.73. Found: C, 66.47; H, 7.72; N, 13.69.

PREPARATION III 2-methyl-5-amino-1H-indole

To a solution of 2.0 gm (11.4 mMol) 2-methyl-5-nitro-1H-indole in 100 mL1:1 ethanol:tetrahydrofuran were added 0.25 gm 5% palladium on carbon.The suspension was hydrogenated at ambient temperature at an initialhydrogen pressure of 60 p.s.i. After 5 hours the reaction mixture wasfiltered and the filtrate concentrated under reduced pressure to give1.5 gm of a dark brown solid. The solid was purified by flashchromatography, eluting with a gradient of dichloromethane containing0-3% methanol, to give 1.19 gm (71.7%) of the title compound as lightbrown plates.

m.p.=154-156° C.; MS(m/e): 147(M+1) Calculated for C₉ H₁₀ N₂ : Theory:C, 73.94; H, 6.89; N, 19.16. Found: C, 74.15; H, 6.93; N, 19.27.

Many of the 5-(C₁ -C₄ alkyl)amino-1H-indoles required for thepreparation of compounds of the invention are available through theprocedure described in Preparation IV.

PREPARATION IV 5-methylamino-1H-indole

A. Preparation of N-ethoxycarbonyl-5-amino-1H-indole

To a solution of 4.27 gm (32.3 mMol) 5-amino-1H-indole in 50 mLtetrahydrofuran were added 5.4 ML (38.8 mMol) triethylamine and thereaction mixture was then cooled to 0° C. To this solution were thenadded dropwise 3.4 mL (35.5 mMol) ethyl chloroformate. After 4 hours thereaction mixture was diluted with 1N HCl and was then extracted withethyl acetate. The organic phase was washed sequentially with 1N HCl,water and saturated aqueous sodium chloride. The remaining organics weredried over sodium sulfate and concentrated under reduced pressure togive 7.4 gm of a dark oil. This oil was purified by flashchromatography, eluting with a gradient of dichloromethane containing0-2.5% methanol, to give 4.95 gm (75%) of the title compound as a tansolid.

m.p.=113-114° C.; MS(m/e): 204(M⁺) Calculated for C₁₁ H₁₂ N₂ O₂ :Theory: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.76; H, 5.92; N, 13.76.

B. Reduction of N-ethoxycarbonyl-5-amino-1H-indole

To a suspension of 6.3 gm (164.5 mMol) lithium aluminum hydride in 50 mLtetrahydrofuran was added dropwise a solution of 4.8 gm (23.5 mMol)N-ethoxycarbonyl-5-amino-1H-indole in 40 mL tetrahydrofuran. Thereaction mixture was heated to reflux until the starting material wasconsumed as measured by thin-layer chromatography. The reaction mixturewas then cooled to ambient and treated with saturated aqueous sodiumsulfate to destroy excess lithium aluminum hydride. The resultingsuspension was filtered and the filtrate concentrated under reducedpressure to give 3.6 gm of a dark solid. The solid was subjected toflash chromatography, eluting with a gradient of dichloromethanecontaining 0-2% methanol, to give 3.3 gm (97.1%) of the title compoundas a tan solid.

MS(m/e): 146(M⁺); Calculated for C₉ H₁₀ N₂ : Theory: C, 73,94; H, 6.90;N, 19.16. Found: C, 73.78; H, 6.94; N, 19.04.

All of the 5-sulfonamido-1H-indoles required for the preparation ofcompounds of the invention are available by treating 5-amino-1H-indolewith an appropriate sulfonyl chloride as described in Preparation V.

PREPARATION V 5-methanesulfonamido-1H-indole

To a solution of 2.0 gm (15.1 mMol) 5-amino-1H-indole in 25 mLtetrahydrofuran were added 2.4 mL (17.2 mMol) triethylamine. Thereaction mixture was cooled in an ice bath as 1.23 mL (15.9 mMol)methanesulfonyl chloride were added dropwise. After 3.5 hours thereaction mixture was partitioned between 1N sodium hydroxide and ethylacetate. The organic phase was extracted twice with 1N sodium hydroxide.All sodium hydroxide phases were combined, adjusted to pH=5 with acidand extracted well with ethyl acetate. These organic phases werecombined, washed sequentially with water and saturated aqueous sodiumchloride, dried over sodium sulfate and concentrated under reducedpressure to give 3.0 gm of a purple solid. This solid was crystallizedfrom cyclohexane/ethyl acetate to give 2.5 gm (78.6%) of the titlecompound as light purple crystals.

m.p.=133-135° C.; MS(m/e): 210(M⁺) Calculated for C₉ H₁₃ N₂ O₂ S:Theory: C, 51.41; H, 4.79; N, 13.32. Found: C, 51.16; H, 4.93; N, 13.27.

PREPARATION VI 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole

A. From 5-nitro-1H-indole

To a solution of 10.38 gm (185 mMol) potassium hydroxide in 200 mLmethanol were added 10.0 gm (61.7 mMol) 5-nitro-1H-indole followed by13.96 gm (123 mMol) 1-methyl-4-piperidone. The mixture was heated toreflux for 4 days under a nitrogen atmosphere. The reaction mixture wasthen allowed to cool to ambient and the solid which formed filtered andwashed with methanol This solid was dried under vacuum at 50° C. Thecombined filtrates were then concentrated under reduced pressure and theresidue subjected to flash chromatography, eluting with 92.5:7.5dichloromethane:methanol. Fractions shown to contain product werecombined and concentrated under reduced pressure. This solid wascombined with that isolated directly from the reaction mixture to give13.79 gm (87%)5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

To a solution of 38.2 gm (145 mMol)5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 1.9 Lethanol and 30 mL 5N HCl were added 10.0 gm 5% palladium on carbon. Thereaction mixture was hydrogenated at ambient for 18 hours with aninitial hydrogen pressure of 60 p.s.i. The reaction mixture was filteredand then concentrated under reduced pressure. The residue was dissolvedin methanol and the solution filtered. This filtrate was concentratedunder reduced pressure and the residue redissolved in ethanol. Thesolution was concentrated to about 500 mL and product allowed tocrystallize. The crystals were filtered to give 48.9 gm (95%) of thetitle compound as its dihydrochloride salt, ethanol solvate.

m.p.=310-320° C. (dec.); MS(m/e): 229(M⁺) Calculated for C₁₄ H₁₉N₃.2HCl.C₂ H₆ O: Theory: C, 55.17; H, 7.81; N, 12.06. Found: C, 55.23;H, 7.61; N, 12.30.

B. Via 5-amino-1H-indole

To a solution of 1.29 gm (20 mMol) potassium hydroxide in 10 mL methanolwere added 1.32 gm (10 mMol) 5-amino-1H-indole followed by 2.46 mL (20mMol) 1-methyl-4-piperidone. The reaction mixture was then heated toreflux for 18 hours. The reaction mixture was cooled to ambient, dilutedwith 20 ml water and the precipitate collected by filtration. The solidwas recrystallized from ethyl acetate:methanol to give 1.11 gm (48.9%)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a tansolid (m.p.=200-203° C.). The tan solid was subjected to flashchromatography, eluting with 100:20:0.5dichloromethane:methanol:ammonium hydroxide, to give 0.99 gm5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a creamcolored solid (m.p.=212-215° C. (ethyl acetate:methanol)).

MS(m/e): 227(M⁺); Calculated for C₁₄ H₁₇ N₃ : Theory: C, 73.98; H, 7.54;N, 18.49. Found: C, 73.76; H, 7.48; N, 18.22.

To a solution of 11.3 gm (50 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 250 mLmethanol were added 3.0 gm 5% palladium on carbon. The mixture washydrogenated at room temperature under an initial hydrogen pressure of60 p.s.i. for 18 hours. The reaction mixture was filtered and thefiltrate concentrated under reduced pressure to give a dark gum whichwas slurried in hexane to give the title compound as a brown solid.

MS(m/e): 229(M⁺)

PREPARATION VII 4-chloro-N-methyl-N-methoxybenzamide

To a solution of 11.38 gm (116.7 mMol) N-methoxy-N-methyl aminehydrochloride in 700 mL 1N sodium hydroxide was added a solution of18.56 gm (106.04 mMol) 4-chlorobenzoyl chloride in 200 mLdichloromethane and the mixture was stirred at ambient. After 18 hoursthe phases were separated and the remaining aqueous was extracted wellwith dichloromethane. All organic phases were combined, dried oversodium sulfate and concentrated under reduced pressure to give 27.9 gm(95%) of the title compound as a clear oil.

MS(m/e): 165(M⁺); IR: 3011, 2974, 2938, 1634 cm⁻¹

PREPARATION VIII5-carboxy-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

To a solution of 5.8 gm (90 mMol) potassium hydroxide in 50 mL methanolwere added 4.83 gm (30 mMol) indole 5-carboxylic acid followed by 7.4 mL(60 mMol) 1-methyl-4-piperidone and the resulting solution was heated atreflux for 18 hours. The reaction mixture was then concentrated underreduced pressure and the resulting oil dissolved in 200 mL water. Thesolution was gradually neutralized by addition of 18 mL 5 N hydrochloricacid. The precipitate which formed was isolated by filtration and washedwith water to provide 6.09 gm after drying. This solid was dissolved in100 mL 0.5 N sodium hydroxide, filtered and the filtrate treated with 50mL 1N hydrochloric acid. The solid which formed was filtered and driedunder reduced pressure to provide 5.46 gm (71%) of the title compound.

m.p.=249° C.; MS(m/e): 256(M⁺) Calculated for C₁₅ H₁₆ N₂ O₂ : Theory: C,70.29; H, 6.29; N, 10.93. Found: C, 70.02; H, 6.39; N, 11.02.

PREPARATION IX 5-carboxy-3-(1-methylpiperidin-4-yl)-1H-indole

5-ethoxycarbonyl-3-(1-methyl-1,2.5.6-tetrahydropyridin-4-yl)-1H-indole

A solution of 0.513 gm (2 mMol)5-carboxy-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole in 5.1mL ethanol was cooled in an ice bath while 0.51 mL sulfuric acid wasadded dropwise. The resulting mixture was heated at reflux for 5 hours.The now homogeneous solution was poured into 50 mL cold water and wasthen made basic with saturated ammonium hydroxide. The light yellowprecipitate was collected by filtration and then recrystallized fromethanol to provide 0.24 gm (42%) of the desired compound as light yellowcrystals.

m.p.=249° C.; MS(m/e): 284(M⁺) Calculated for C₁₇ H₂₀ N₂ O₂ : Theory: C,71.81; H, 7.09; N, 9.85. Found: C, 71.97; H, 7.25; N, 9.71.

5-ethoxycarbonyl-3-(1-methylpiperidin-4-yl)-1H-indole

To a solution of 3.24 gm (11.3 mMol)5-ethoxycarbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indolein 100 mL ethanol was added 0.8 gm 5% palladium an carbon and thereaction mixture hydrogenated at room temperature for 18 hours at aninitial hydrogen pressure of 60 p.s.i. The reaction mixture was filteredand the filtrate concentrated under reduced pressure. The residual oil,which crystallized on standing at room temperature, was recrystallizedfrom 30 mL acetonitrile to provide 1.79 gm (55%) of the desired compoundas colorless crystals.

m.p.=155-157° C.; MS(m/e): 286(M⁺) Calculated for C₁₇ H₂₂ N₂ O₂ :Theory: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.07; H, 7.88; N, 9.73.

Saponification/Protonation

A mixture of 0.859 gm (3 mMol)5-ethoxycarbonyl-3-(1-methylpiperidin-4-yl)-1H-indole, 6.0 mL ethanoland 6 mL 2N sodium hydroxide were heated at reflux for 2 hours. Ethanolwas distilled from the resulting solution and the remaining aqueoussolution was neutralized with 2.4 mL 5N hydrochloric acid. The resultingoil suspended in water is treated with a small amount of dichloromethaneand cooled. The resulting solid is filtered, washed with water andacetone, and then recrystallized from 15 mL water to provide 0.308 gm(40%) of the title compound as colorless crystals.

m.p.>280° C.; MS(m/e): 258(M⁺) Calculated for C₁₅ H₁₈ N₂ O₂ : Theory: C,69.74; H, 7.02; N, 10.84. Found: C, 69.66; H, 7.03; N, 10.92.

PREPARATION X Preparation of a Polystyrene Bound Isocyanate Resin

To a stirred suspension of 50 gm (61 mMol) aminomethylated polystyreneresin (1.22 mMol/gm) in 800 mL toluene was added 193 mL (366 mMol) 1.9 Mphosgene in toluene. After stirring the reaction mixture for 10 minutes,67 mL (482 mMol) triethylamine was added and the reaction mixture wasstirred for 18 hours at room temperature. The mixture was filtered andthe recovered solid washed with 10 times with dichloromethane. A lightpink resin mixed with a white solid was obtained. This solid mixture wasresuspended in 700 mL dichloromethane, stirred for 10 minutes and thenfiltered and washed well with dichloromethane. The resulting solid wasagain suspended, stirred and washed with dichloromethane to provide thedesired resin.

IR(KBr): 2252 cm⁻¹ (characteristic peak for --N═C═O)

EXAMPLE 1 5-phenylthio-3-(1-methylpiperidin-4-yl)-1H-indole

To a suspension of 0.21 gm (1.05 mMol) potassium hydride in 5.0 mLtetrahydrofuran at 0° C. was added a solution of 0.3 gm (1.0 mMol)5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole in 5.0 mL tetrahydrofuranand the solution stirred for about 30 minutes. The resulting mixture wascooled to about -78° C. and to it were added 1.47 mL (2.3 mMol)t-butyllithium, which had been precooled to -78° C., via cannula. Afterabout 15 minutes, 0.43 gm (2 mMol) diphenyl disulfide were added and thereaction mixture was allowed to warm gradually to ambient. The reactionmixture was then treated with 5N sodium hydroxide and extracted withdiethyl ether. The ether extracts were combined, washed with saturatedaqueous sodium chloride, dried over sodium sulfate and concentratedunder reduced pressure. Purification by flash chromatography, elutingwith 4.5:0.5:0.2 ethyl acetate:methanol:toluene, followed byrecrystallization from hexane:diethyl ether gave 0.28 gm (85.1%) of thetitle compound as a white solid.

m.p.=147-150° C.; MS(m/e): 322(M⁺) Calculated for C₂₀ H₂₂ N₂ S: Theory:C, 74.49; H, 6.89; N, 8.69. Found: C, 74.27; H, 6.96; N, 8.77.

The compounds of Examples 2-5 were prepared employing the methoddescribed in detail in Example 1.

EXAMPLE 2 5-(4-methoxyphenyl)thio-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.3 gm (1.0 mMol) 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole and0.55 gm (1.99 mMol) di(4-methoxyphenyl) disulfide gave 0.28 gm (64.0%)of the title compound as a colorless solid.

m.p.=160-162° C.; MS(m/e): 352(M⁺) Calculated for C₂₁ H₂₄ N₂ OS: Theory:C, 71.55; H, 6.86; N, 7.95. Found: C, 71.67; H, 6.89; N, 8.24.

EXAMPLE 3 5-benzylthio-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.325 gm (1.11 mMol) 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indoleand 0.55 gm (2.22 mMol) dibenzyl disulfide gave 0.065 gm (17.0%) of thetitle compound as a colorless solid.

m.p.=138-141° C.; MS(m/e): 336(M⁺) Calculated for C₂₁ H₂₄ N₂ S: Theory:C, 74.96; H, 7.19; N, 8.33. Found: C, 75.55; H, 7.32; N, 7.95.

EXAMPLE 4 5-(pyridin-2-yl)thio-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.3 gm (1.0 mMol) 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole and0.44 gm (1.99 mMol) di(pyridin-2-yl) disulfide gave 0.12 gm (37.0%) ofthe title compound as an off-white solid.

m.p.=83° C.; MS(m/e): 323(M⁺) Calculated for C₁₉ H₂₁ N₃ S: Theory: C,70.55; H, 6.54; N, 12.99. Found: C, 70.25; H, 6.60; N, 12.80.

EXAMPLE 5 5-(4-chlorophenyl)thio-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.4 gm (1.36 mMol) 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indoleand 0.78 gm (2.73 mMol) di(4-chlorophenyl) disulfide gave 0.39 gm(79.6%) of the title compound as a colorless solid.

m.p.=148-150° C.; MS(m/e): 356(M⁺) Calculated for C₂₀ H₂₁ N₂ SCl:Theory: C, 67.30; H, 5.93; N, 7.85. Found: C, 67.47; H, 6.10; N, 7.84.

EXAMPLE 6 5-benzoyl-3-(1-methylpiperidin-4-yl)-1H-indole

To a solution of 0.41 mL (0.73 mMol) phenyllithium in 4.0 mLtetrahydrofuran at 0° C. were added 0.10 gm (0.33 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) in 2.0 mL tetrahydrofuran. After 1 hour the reactionmixture was quenched with 2N sodium hydroxide and the mixture extractedwell with diethyl ether. The ether extracts were then washed withsaturated aqueous sodium chloride, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by radialchromatography (2 mm silica), eluting with 10:1dichloromethane:methanol, to give 0.096 gm (91%) of the title compoundas a light yellow solid.

m.p.=101° C.; MS(m/e): 319(M⁺) IR: 1644 cm⁻¹ Calculated for C₂₁ H₂₂ N₂O.H₂ O: Theory: C, 74.48; H, 7.19; N, 8.33. Found: C, 74.85; H, 7.00; N,8.67.

The compounds of Examples 7-9 were prepared employing the methoddescribed in detail in Example 6.

EXAMPLE 7 5-acetyl-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloridemonohydrate

Using 0.30 gm (1.0 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 3.56 mL (4.98 mMol) methyllithium gave5-acetyl-3-(1-methylpiperidin-4-yl)-1H-indole which was converted to itshydrochloride salt. 0.153 gm (60%) of the title compound were recovered.

m.p.=65° C.; MS(m/e): 256(M⁺) Calculated for C₁₆ H₂₀ N₂ O.HCl.H₂ O:Theory: C, 61.82; H, 7.46; N, 9.01. Found: C, 62.13; H, 7.86; N, 9.24.

EXAMPLE 8 5-pentanoyl-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloride

Using 0.20 gm (0.66 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 1.66 mL (2.67 mMol) n-butyllithium gave5-pentanoyl-3-(1-methylpiperidin-4-yl)-1H-indole which was converted toits hydrochloride salt. 0.124 gm (63%) of the title compound wererecovered as a tan solid which was crystallized from ethanol:diethylether.

m.p.=242-245° C.; MS(m/e): 299(M⁺) Calculated for C₁₉ H₂₆ N₂ O.HCl:Theory: C, 68.15; H, 8.13; N, 8.37. Found: C, 67.89; H, 8.05; N, 8.64.

EXAMPLE 9 5-phenylacetyl-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.30 gm (1.0 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 2.5 mL (5.0 mMol) benzylmagnesium chloride gave0.22 gm (66%) of the title compound as an off-white solid.

m.p.=69° C.; MS(m/e): 333(M⁺) IR: 1662 cm⁻¹ Calculated for C₂₂ H₂₄ N₂ O:Theory: C, 79.48; H, 7.28; N, 8.43. Found: C, 79.68; H, 7.47; N, 8.61.

EXAMPLE 10 5-(4-methoxybenzoyl)-3-(1-methylpiperidin-4-yl)-1H-indole

To a solution of 0.35 mL (2.82 mMol) 4-methoxy-1-bromobenzene in 3.0 mLtetrahydrofuran at -78° C. were added 1.83 mL (2.93 mMol) n-butyllithiumand the reaction mixture stirred for 30 minutes at -78° C. To thissolution were then added 0.17 gm (0.56 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) in 2.0 mL tetrahydrofuran. The reaction mixture wasallowed to warm gradually to ambient and was then quenched with 2Nsodium hydroxide. The resulting mixture was extracted well with diethylether. The ether extracts were then washed with saturated aqueous sodiumchloride, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by radial chromatography (2 mmsilica), eluting with 10:1 dichloromethane:methanol, to give 0.135 gm(72%) of the title compound as a light yellow solid.

MS(m/e): 349(M⁺) Calculated for C₂₂ H₂₄ N₂ O₂ : Theory: C, 75.84; H,6.94; N, 8.04. Found: C, 75.85; H, 7.11; N, 8.06.

The compounds of Examples 11-19 were prepared employing the methoddescribed in detail in Example 10.

EXAMPLE 11 5-(4-fluorobenzoyl)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.20 gm (0.66 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 0.36 mL (4.98 mMol) 4-fluoro-1-bromobenzene gave0.158 gm (71%) of the title compound as an off-white solid.

m.p.=89° C.; MS(m/e): 336(M⁺)

EXAMPLE 12 5-(4-methylbenzoyl)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.20 gm (0.66 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 0.41 mL (3.32 mMol) 4-methyl-1-bromobenzene gave0.180 gm (79%) of the title compound as a yellow solid.

m.p.=92° C.; MS(m/e): 332(M⁺) Calculated for C₂₂ H₂₄ N₂ O: Theory: C,79.48; H, 7.28; N, 8.43. Found: C, 79.60; H, 7.40; N, 8.54.

EXAMPLE 135-(4-trifluoromethylbenzoyl)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.15 gm (0.50 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 0.35 mL (2.49 mMol)4-trifluoromethyl-1-bromobenzene gave 0.122 gm (64%) of the titlecompound as a yellow solid.

m.p.=160-162° C.; MS(m/e): 386(M⁺) Calculated for C₂₂ H₂₁ N₂ OF₃ :Theory: C, 68.38; H, 5.48; N, 7.25. Found: C, 68.54; H, 5.72; N, 7.47.

EXAMPLE 145-(4-trifluoromethoxybenzoyl)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.17 gm (0.56 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 0.49 mL (3.32 mMol)4-trifluoromethoxy-1-bromobenzene gave 0.157 gm (69%) of the titlecompound as a light yellow solid.

m.p.=172-175° C.; MS(m/e): 402(M⁺) Calculated for C₂₂ H₂₁ N₂ O₂ F₃ :Theory: C, 65.66; H, 5.26; N, 6.96. Found: C, 65.86; H, 5.45; N, 7.20.

EXAMPLE 155-(4-dimethylaminobenzoyl)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.20 gm (0.66 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 0.80 gm (3.98 mMol) 4-dimethylamino-1-bromobenzenegave 0.159 gm (66%) of the title compound as a light yellow solid.

m.p.=103-104° C.; MS(m/e): 361(M⁺) Calculated for C₂₃ H₂₇ N₃ O.0.5 H₂ O:Theory: C, 74.56; H, 7.62; N, 11.34. Found: C, 74.46; H, 7.53; N, 11.04.

EXAMPLE 16 5-(2-naphthoyl)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.20 gm (0.66 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 0.60 gm (3.32 mMol) 2-bromonaphthalene gave 0.178gm (73%) of the title compound as a light yellow solid.

m.p.=92° C.; MS(m/e): 368(M⁺)

EXAMPLE 17 5-(2-pyridinecarbonyl)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.20 gm (0.66 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 0.32 mL (3.32 mMol) 2-bromopyridine gave 0.089 gm(42%) of the title compound as a light yellow solid.

m.p.=90° C.; MS(m/e): 319(M⁺)

EXAMPLE 18 5-(N-phenylcarboxamido)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 0.20 gm (0.66 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 0.30 mL (3.32 mMol) aniline gave 0.118 gm (53%) ofthe title compound as a light tan solid.

m.p.=97° C.; MS(m/e): 333(M⁺) Calculated for C₂₁ H₂₃ N₃ O.0.25 H₂ O:Theory: C, 74.64; H, 7.01; N, 12.43. Found: C, 74.29; H, 7.06; N, 12.51.

EXAMPLE 19 5-(N-benzylcarboxamido)-3-(1-methylpiperidin-4-yl)-1H-indole

Using 1.2 gm (4.0 mMol)N-methyl-N-methoxy-5-carboxamido-3-(1-methylpiperidin-4-yl)-1H-indole(Preparation II) and 2.2 mL (20.0 mMol) benzylamine gave 0.788 gm (57%)of the title compound as a white solid.

m.p.=87° C.; MS(m/e): 347(M⁺) Calculated for C₂₂ H₂₅ N₃ O: Theory: C,76.05; H, 7.25; N, 12.09. Found: C, 76.06; H, 7.51; N, 12.35.

EXAMPLE 20 5-(4-chlorobenzoyl)-3-(1-methylpiperidin-4-yl)-1H-indole

To a suspension of 0.21 gm (1.05 mMol) potassium hydride in 5.0 mLtetrahydrofuran at 0° C. were added a solution of 0.3 gm (1.0 mMol)5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole in 5.0 mL tetrahydrofuranand the solution stirred for about 30 minutes. The resulting mixture wascooled to about -78° C. and to it were added 1.47 mL (2.3 mMol)t-butyllithium, which had been precooked to -78° C., via cannula. Afterabout 15 minutes, a solution of 1.0 gm (5.0 mMol)N-methyl-N-methoxy-4-chlorobenzamide (Preparation VII) in 3.0 mLtetrahydrofuran were added. The reaction mixture was allowed togradually warm to ambient and was then quenched with 2N sodiumhydroxide. The mixture extracted well with diethyl ether and the etherextracts were then washed with saturated aqueous sodium chloride, driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by radial chromatography (2 mm silica), eluting with 95:5ethyl acetate:methanol, to give the title compound as a light yellowsolid.

m.p.=133° C.; MS(m/e): 352(M⁺) Calculated for C₂₁ H₂₁ N₂ OCl.0.5H₂ O:Theory: C, 69.70; H, 6.13; N, 7.74. Found: C, 70.02; H, 6.20; N, 7.93.

EXAMPLE 215-methanesulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

To a solution of 1.2 gm (21.4 mMol) potassium hydroxide in 12 mLmethanol was added 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indolefollowed by 0.76 mL (6.2 mMol) 1-methyl-4-piperidone. The homogeneoussolution was heated to reflux for 18 hours under nitrogen. The reactionmixture was then cooled and concentrated under reduced pressure. Theresidue was dissolved in water and the pH of the solution adjusted from14 to 8-9 by the addition of acid. The precipitate that formed wasfiltered, washed with water and dried under vacuum to give 1.3 gm(89.6%) of the title compound as a tan solid.

m.p.=210-214° C.; MS(m/e): 305(M⁺) Calculated for C₁₅ H19N₃ O₂ S:Theory: C, 58.99; H. 6.27; N, 13.76. Found: C, 59.00; H, 6.20; N, 13.74.

The compounds of Examples 22-29 were prepared employing the proceduredescribed in detail in Example 21.

EXAMPLE 22N-methyl-5-methanesulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.23 gm (5.5 mMol)N-methyl-5-methanesulfonylamino-1H-indole and 0.88 mL (7.1 mMol)1-methyl-4-piperidone, 1.4 gm (80%) of the title compound were recoveredas a tan, crystalline powder.

m.p.=198-202° C.; MS(m/e): 319(M⁺) Calculated for C₁₆ H₂₁ N₃ O₂ S:Theory: C, 60.16; H, 6.63; N, 13.16. Found: C, 60.30; H, 6.76; N, 12.97.

EXAMPLE 232-methyl-5-methanesulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.37 gm (6.1 mMol)2-methyl-5-methanesulfonylamino-1H-indole and 0.98 mL (7.9 mMol)1-methyl-4-piperidone, 0.65 gm (33.3%) of the title compound wererecovered as a yellow solid.

m.p.=176-184° C.; MS(m/e): 320(M+1) Calculated for C₁₆ H₂ N₃ O₂ S:Theory: C, 60.16; H, 6.63; N, 13.16. Found: C, 60.39; H, 6.48; N, 13.10.

EXAMPLE 245-ethanesulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.45 gm (6.5 mMol) 5-ethanesulfonylamino-1H-indole and1.03 mL (3.4 mMol) 1-methyl-4-piperidone, 1.23 gm (59.7%) of the titlecompound were recovered as pale orange crystals.

m.p.=224-226° C.; MS(m/e): 319(M⁺) Calculated for C₁₆ H₂₁ N₃ O₂ S:Theory: C, 60.16; H, 6.63; N, 13.16. Found: C, 60.45; H, 6.69; N, 13.22.

EXAMPLE 255-(N,N-dimethylamino)sulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.17 gm (4.89 mMol)5-(N,N-dimethylamino)sulfonylamino-1H-indole and 0.78 mL (6.4 mMol)1-methyl-4-piperidone, 1.19 gm (72.6%) of the title compound wererecovered as a pale yellow powder.

m.p.=207-208° C.; MS(m/e): 334(M⁺) Calculated for C₁₆ H₂₂ N₄ O₂ S:Theory: C, 57.46; H, 6.63; N, 16.75. Found: C, 57.69; H, 6.71; N, 16.60.

EXAMPLE 265-methanesulfonylamino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.50 gm (7.1 mMol) 5-methanesulfonylamino-1H-indole and1.25 mL (9.3 mMol) 1-ethyl-4-piperidone, 1.34 gm (58.8%) of the titlecompound were recovered as a light yellow, crystalline powder.

m.p.=218-219° C. (dec.); MS(m/e): 320(M+1) Calculated for C₁₆ H₂₁ N₃ O₂S: Theory: C, 60.16; H, 6.63; N, 13.16. Found: C, 59.89; H, 6.39; N,13.24.

EXAMPLE 275-methanesulfonylamino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.50 gm (7.1 mMol) 5-methanesulfonylamino-1H-indole and1.4 mL (9.3 mMol) 1-propyl-4-piperidone, 2.1 gm (88.2%) of the titlecompound were recovered as a yellow powder.

m.p.=217-218.5° C. (dec.); MS(m/e): 334(M+1) Calculated for C₁₇ H₂₃ N₃O₂ S: Theory: C, 61.23; H, 6.95; N, 12.60. Found: C, 61.51; H, 7.23; N,12.30.

EXAMPLE 285-methanesulfonylamino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and0.873 gm (6.2 mMol) 1-isopropyl-4-piperidone, 1.02 gm (64.2%) of thetitle compound were recovered as a tan powder.

m.p.=211-213° C. (dec.); MS(m/e): 333(M⁺) Calculated for C₁₇ H₂₃ N₃ O₂S: Theory: C, 61.23; H, 6.95; N, 12.60. Found: C, 60.95; H, 6.87; N,12.60.

EXAMPLE 295-methanesulfonylamino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and0.96 gm (6.2 mMol) 1-butyl-4-piperidone, 1.4 gm (84.8%) of the titlecompound were recovered as a yellow powder.

m.p.=202-204° C.; MS(m/e): 347(M⁺) Calculated for C₁₈ H₂₅ N₃ O₂ S:Theory: C, 62.22; H, 7.25; N, 12.09. Found: C, 62.10; H, 7.11; N, 12.28.

EXAMPLE 30 5-methanesulfonylamino-3-(1-methylpiperidin-4-yl)-1H-indoleoxalate

To a solution 0.815 gm (2.67 mMol)5-methanesulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolein 125 mL methanol were added 0.815 gm 5% palladium on carbon. Themixture was hydrogenated at ambient for 18 hours with an initialhydrogen pressure of 60 p.s.i. The reaction mixture was filtered and thefiltrate concentrated under reduced pressure. The residual oil waspurified by flash chromatography, eluting with 90:10dichloromethane:methanol. Fractions shown to contain product werecombined and concentrated under reduced pressure. The residue wasdissolved in methanol and to it were added oxalic acid. The suspensionwas filtered to give 0.261 gm (25%) of the title compound.

m.p.=119.1° C.; MS(m/e): 307(M⁺)

EXAMPLE 315-(N-methyl)methanesulfonylamino-3-(1-methylpiperidin-4-yl)-1H-indole

Following the procedure described in detail in Example 30, 0.807 gm(2.53 mMol)5-(N-methyl)methanesulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(Example 22) was hydrogenated to give 0.075 gm (9.3%) of the titlecompound as a tan foam.

MS(m/e): 322(M+1) Calculated for C₁₆ H₂₃ N₃ O₂ S: Theory: C, 59.79; H,7.21; N, 13.07. Found: C, 59.62; H, 7.33; N, 12.82.

EXAMPLE 322-methyl-5-methanesulfonylamino-3-(1-methylpiperidin-4-yl)-1H-indole

To a solution of 0.45 gm (1.41 mMol)2-methyl-5-methanesulfonylamino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(Example 23) in 125 mL methanol were added 0.11 gm 5% palladium oncarbon and the reaction mixture hydrogenated at ambient temperature withan initial hydrogen pressure of 60 p.s.i. After 18 hours the reactionmixture was filtered and the filtrate concentrated under reducedpressure to give a yellow oil. The oil was purified by radialchromatography (2 mm silica gel), eluting with 100:5:0.5dichloromethane:methanol:ammonium hydroxide, to give 0.21 gm of a yellowfoam which was then precipitated from ethyl acetate/hexanes to give 0.18gm (39.7%) of the title compound as a white powder.

m.p.=124-128° C.; MS(m/e): 321(M⁺) Calculated for C₁₆ H₂₃ N₃ O₂ S:Theory: C, 59.79; H, 7.21; N, 13.07. Found: C, 59.88; H, 7.24; N, 13.33.

The compounds of Examples 33-38 were prepared by the procedure describedin detail in Example 32.

EXAMPLE 33 5-ethanesulfonylamino-3-(1-methylpiperidin-4-yl)-1H-indole

0.70 gm (2.2 mMol)5-ethanesulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(Example 24) were hydrogenated to give 0.545 gm (77.4%) of the titlecompound as a white powder.

m.p.=176-178° C.; MS(m/e): 322(M+1) Calculated for C₁₆ H₂₃ N₃ O₂ S:Theory: C, 59.79; H, 7.21; N, 13.07. Found: C, 60.07; H, 7.22; N, 12.79.

EXAMPLE 345-(N,N-dimethylamino)sulfonylamino-3-(1-methylpiperidin-4-yl)-1H-indole

0.66 gm (2.0 mMol)5-(N,N-dimethylamino)sulfonylamino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(Example 25) were hydrogenated to give 0.333 gm (50.2%) of the titlecompound as an off-white powder.

m.p.=179-181° C. (dec.); MS(m/e): 336(M⁺) Calculated for C₁₆ H₂₄ N₄ O₂S: Theory: C, 57.12; H, 7.19; N, 16.65. Found: C, 57.38; H, 7.27; N,16.87.,

EXAMPLE 35 5-methanesulfonylamino-3-(1-ethylpiperidin-4-yl)-1H-indole

0.96 gm (3.0 mMol)5-methanesulfonylamino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(Example 26) were hydrogenated to give 0.531 gm (55.0%) of the titlecompound as an off-white powder.

m.p.=179-181° C.; MS(m/e): 321(M⁺) Calculated for C₁₆ H₂₃ N₃ O₂ S:Theory: C, 59.79; H, 7.21; N, 13.07. Found: C, 59.50; H, 7.11; N, 12.81.

EXAMPLE 36 5-methanesulfonylamino-3-(1-propylpiperidin-4-yl)-1H-indole

1.0 gm (3.0 mMol)5-methanesulfonylamino-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(Example 27) were hydrogenated to give 0.376 gm (37.2%) of the titlecompound as an off-white powder.

m.p.=87-90° C.; MS(m/e): 335(M⁺) Calculated for C₁₇ H₂₅ N₃ O₂ S: Theory:C, 60.87; H, 7.51; N, 12.53. Found: C, 61.12; H, 7.32; N, 12.70.

EXAMPLE 375-methanesulfonylamino-3-(1-isopropylpiperidin-4-yl)-1H-indole

0.75 gm (2.25 mMol)5-methanesulfonylamino-3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(Example 28) were hydrogenated to give 0.310 gm (41.1%) of the titlecompound as a white powder.

m.p.=104-108° C.; MS(m/e): 335(M⁺) Calculated for C₁₇ H₂₅ N₃ O₂ S.C₂ H₂O₄ : Theory: C, 53.63; H, 6.40; N, 9.87. Found: C, 53.38; H, 6.34; N,9.66.

EXAMPLE 38 5-methanesulfonylamino-3-(1-butylpiperidin-4-yl)-1H-indole

1.05 gm (3.02 mMol)5-methanesulfonylamino-3-(1-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(Example 29) were hydrogenated to give 0.255 gm (24.0%) of the titlecompound as a tan foam.

m.p.=78° C.; MS(m/e): 349(M⁺) Calculated for C₁₈ H₂₇ N₃ O₂ S: Theory: C,61.86; H, 7.79; N, 12.02. Found: C, 61.66; H, 7.74; N, 11.87.

EXAMPLE 39 5-benzenesulfonylamino-3-(1-methylpiperidin-4-yl)-1H-indole

To a solution of 2.00 gm (5.74 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 50.0 mL dichloromethanewere added 1.63 gm (20.7 mMol) pyridine and the solution was cooled to0° C. To this cooled solution were then added dropwise a solution of2.23 gm (12.6 mMol) benzenesulfonyl chloride in 50 mL dichloromethane.The reaction mixture was allowed to warm gradually to ambient. After 24hours the reaction mixture was washed with 100 mL water and theremaining organics concentrated under reduced pressure. The residue wassuspended in water and the pH adjusted to 14 with sodium hydroxide. Theaqueous phase was then extracted well with dichloromethane. The organicphase was washed sequentially with water and saturated aqueous sodiumchloride, dried over sodium sulfate and concentrated under reducedpressure. The aqueous phases were combined and the pH adjusted to 10 bythe addition of acid and extracted again with 3:1chloroform:isopropanol. These organic extracts were combined andconcentrated under reduced pressure. The combined residues weresubjected to flash chromtography, eluting with a gradient system of100:10:0.5 to 100:11:0.5 dichloromethane:methanol:ammonium hydroxide,giving 0.83 gm (39.1%) of the title compound as a white powder.

m.p.=246-249° C. (dec.); MS(m/e): 370(M+1) Calculated for C₂₀ H₂₃ N₃ O₂S: Theory: C, 65.02; H, 6.27; N, 11.37. Found: C, 64.78; H, 6.09; N,11.44.

EXAMPLE 405-(4-iodobenzenesulfonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Following the procedure described in detail in Example 39, 0.791 gm(3.45 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 1.1 gm(3.62 mMol) 4-iodobenzenesulfonyl chloride were used to prepare 0.809(47.3%) of the title compound as a white powder.

m.p.>250° C.; MS(m/e): 495(M⁺) Calculated for C₂₀ H₂₂ IN₃ O₂ S: Theory:C, 48.49; H, 4.48; N, 8.48. Found: C, 48.68; H, 4.47; N, 8.26.

EXAMPLE 415-(di(trifluoromethanesulfonyl))amino-3-(1-methylpiperidin-4-yl)-1H-indolehydrochloride

To a suspension of 1.00 gm (2.87 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride in 100 mLdichloromethane were added 2.5 mL (14.3 mMol) diisopropylethylaminefollowed by 1.06 mL (6.3 mMol) trifluoromethanesulfonic anhydride. After20 minutes the reaction mixture was washed with water, dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography, eluting with dichloromethanecontaining 15% methanol, to give5-(di(trifluoromethanesulfonyl))amino-3-(1-methylpiperidin-4-yl)-1H-indole.This material was converted to its hydrochloride salt and wascrystallized from acetonitrile to give 0.34 gm (22.3%) of the titlecompound.

m.p.=175-185° C. (dec.); MS(m/e): 493(M⁺) Calculated for C₁₆ H₁₇ N₃ O₄S₂ F₆.HCl: Theory: C, 36.27; H, 3.23; N, 7.93. Found: C, 36.48; H, 3.58;N, 7.85.

EXAMPLE 42 5-(methoxycarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

To a mixture of 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 15.0 mg (0.131 mMol)polyvinyl-pyridine in 3.0 mL dichloromethane were added 4.3 mg (0.0458mMol) methyl chloroformate. The reaction mixture was mixed for 18 hoursat ambient temperature. To this mixture were then added 170 mg (0.137mMol) aminomethylated polystyrene and the reaction mixed for anadditional 18 hours. The reaction mixture was then filtered and thevolatiles evaporated to give 10.2 mg (81%) of the title compound.

MS(m/e): 287(M⁺)

The compounds of Examples 43-50 were prepared by the procedure describedin detail in Example 42.

EXAMPLE 43 5-(ethoxycarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 4.97 mg (0.0458 mMol)ethyl chloroformate, 11.1 mg (84%) of the title compound were recovered.

MS(m/e): 301(M⁺)

EXAMPLE 44 5-(propoxycarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 5.62 mg (0.0458 mMol)propyl chloroformate, 11.2 mg (81%) of the title compound wererecovered.

MS(m/e): 316(M⁺)

EXAMPLE 455-(allyloxycarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 5.5 mg (0.0458 mMol)allyl chloroformate, 9.7 mg (71%) of the title compound were recovered.

MS(m/e). 314(M⁺)

EXAMPLE 465-((2-methoxyethyl)carbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.0567 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 8.65 mg (0.062 mMol)2-methoxyethyl chloroformate, 10.25 mg (54%, of the title compound wererecovered.

MS(m/e): 332(M⁺)

EXAMPLE 475-(cyclopentyloxycarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.0567 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.27 mg (0.062 mMol)cyclopentyl chloroformate, 18.1 mg (93%) of the title compound wererecovered.

MS(m/e): 342(M⁺)

EXAMPLE 48 5-(phenoxycarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 7.2 mg (0.0458 mMol)phenyl chloroformate, 13.9 mg (91%) of the title compound wererecovered.

MS(m/e): 350(M⁺)

EXAMPLE 495-(4-methoxyphenyl)oxycarbonyl)amino-3-l(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.0567 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.062 mMol)4-methoxyphenyl chloroformate, 13.4 mg (63%) of the title compound wererecovered.

MS(m/e): 380(M⁺)

EXAMPLE 505-(4-chlorophenyl)oxycarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.0567 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.062 mMol)4-chlorophenyl chloroformate, 18.1 mg (93%) of the title compound wererecovered.

MS(m/e):

EXAMPLE 51 N-methyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

To a solution of 2.0 gm (5.74 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloridemono-ethanolate and 5.0 mL (36 mMol) triethylamine in 100 mLdichloromethane were added 0.74 mL (12.6 mMol) methyl isocyanate. Thereaction mixture was stirred for 15 minutes and was then washed with 100mL of water. The remaining organics were dried over sodium sulfate andconcentrated under reduced pressure. The resultant residue wascrystallized from acetonitrile to give 1.05 gm (64%) of the titlecompound.

MS(m/e): 287(M+1); Calculated for C₁₆ H₂₂ N₄ O: Theory: C, 69.11; H,7.74; N, 19.56. Found: C, 69.37; H, 7.82; N, 19.67.

EXAMPLE 52 N-phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)ureahydrochloride

To a solution of 2.0 gm (5.74 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloridemono-ethanolate and 5.0 mL (36 mMol) triethylamine in 100 mLdichloromethane were added 1.37 mL (12.6 mMol) phenyl isocyanate. Thereaction mixture was stirred for 15 minutes and was then washed with 100mL of water. The remaining organics were dried over sodium sulfate andconcentrated under reduced pressure. The resultant residue wascrystallized from acetonitrile to give 1.40 gm (70%)N-phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea. Thismaterial was dissolved in methanol and to it was added an equivalent ofmethanolic hydrogen chloride. The solution was then concentrated underreduced pressure and the residual oil crystallized from ethanol to givethe title compound.

m.p.=215-220° C.; MS(m/e): 348(M⁺) Calculated for C₂₁ H₂₄ N₄ O.HCl:Theory: C, 65.53; H, 6.55; N, 14.56. Found: C, 65.27; H, 6.43; N, 14.35.

EXAMPLE 53 N-ethyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

To a solution of 15.0 mg (0.0655 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 3.0 mL chloroform wereadded 9.3 mg (0.131 mMol) ethyl isocyanate. The reaction was mixed for48 hours and to it were then added 0.23 gm (0.131 mMol) aminomethylatedpolystyrene and the reaction mixed for an additional 18 hours. Thereaction mixture was then filtered and the volatiles evaporated to give16.1 mg (82%) of the title compound.

MS(m/e):

The compounds of Examples 54-75 were prepared by the procedure describedin detail in Example 53.

EXAMPLE 54 N-propyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol)propyl isocyanate, 5.8 mg of the title compound were recovered.

MS(m/e): 315(M⁺)

EXAMPLE 55 N-allyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol)allyl isocyanate, 19.6 mg (96%) of the title compound were recovered.

MS(m/e): 313(M⁺)

EXAMPLE 56 N-isopropyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.13 mg (0.131 mMol)isopropyl isocyanate, 21.9 mg of the title compound were recovered.

MS(m/e): 315(M⁺)

EXAMPLE 57 N-n-butyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol)n-butyl isocyanate, 20.6 mg (96%) of the title compound were recovered.

MS(m/e): 329(M⁺)

EXAMPLE 58N-cyclohexyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 16.37 mg (0.131 mMol)cyclohexyl isocyanate, 20.1 mg (87%) of the title compound wererecovered.

MS(m/e): 355(M⁺)

EXAMPLE 59N-(1-ethoxycarbonyl-2-methylpropyl)-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 14.56 mg (0.0852 mMol)ethyl 2-isocyanato-3-methylbutyrate, 25.0 mg (95%) of the title compoundwere recovered.

MS(m/e): 401(M⁺)

EXAMPLE 60N-(4-fluoro)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.9 mg (0.072 mMol)4-fluorophenyl isocyanate, 20.7 mg (86%) of the title compound wererecovered.

MS(m/e): 367(M⁺)

EXAMPLE 61N-(4-chloro)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.0 mg (0.072 mMol)4-chlorophenyl isocyanate, 21.4 mg (86%) of the title compound wererecovered.

MS(m/e): 383(M⁺)

EXAMPLE 62N-(4-methyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.6 mg (0.072 mMol)4-methylphenyl isocyanate, 23.7 mg (99%) of the title compound wererecovered.

MS(m/e): 363(M⁺)

EXAMPLE 63N-(3-trifluoromethyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 16.0 mg (0.0852 mMol)3-trifluoromethylphenyl isocyanate, 26.0 mg (95%) of the title compoundwere recovered.

MS(m/e): 417(M⁺)

EXAMPLE 64N-(4-methoxy)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 10.7 mg (0.072 mMol)4-methoxyphenyl isocyanate, 22.4 mg (91%) of the title compound wererecovered.

MS(m/e): 379(M⁺)

EXAMPLE 65N-(2-methoxy)phenyl-N-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 10.7 mg (0.072 mMol)2-methoxyphenyl isocyanate, 21.7 mg (88%) of the title compound wererecovered.

MS(m/e): 379(M⁺)

EXAMPLE 66N-(4-methylthio)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 14.05 mg (0.0852 mMol)4-methylthiophenyl isocyanate, 24.1 mg (93%) of the title compound wererecovered.

MS(m/e): 395(M⁺)

EXAMPLE 67N-(3-acetyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 13.7 mg (0.0852 mMol)3-acetylphenyl isocyanate, 25.0 mg (98%) of the title compound wererecovered.

MS(m/e): 391(M⁺)

EXAMPLE 68N-(4-butoxycarbonyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 15.8 mg (0.072 mMol)4-carbobutoxyphenyl isocyanate, 27.1 mg (92%) of the title compound wererecovered.

MS(m/e): 449(M⁺)

EXAMPLE 69N-(2-phenyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 16.6 mg (0.0852 mMol)2-phenylphenyl isocyanate, 26.7 mg (96%) of the title compound wererecovered.

MS(m/e): 425(M⁺)

EXAMPLE 70N-(4-phenyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 16.6 mg (0.0852 mMol)4-phenylphenyl isocyanate, 26.2 mg (95%) of the title compound wererecovered.

MS(m/e): 425(M⁺)

EXAMPLE 71N-(2,3-dichloro)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 16.0 mg (0.0852 mMol)2,3-dichlorophenyl isocyanate, 26.7 mg (98%) of the title compound wererecovered.

MS(m/e): 417(M⁺)

EXAMPLE 72 N-benzyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.32 mg (0.0852 mMol)benzyl isocyanate, 9.4 mg of the title compound were recovered.

MS(m/e): 363(M⁺)

EXAMPLE 73 N-phenethyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol)2-phenethyl isocyanate, 15.8 mg (65%) of the title compound wererecovered.

MS(m/e): 377(M⁺)

EXAMPLE 74N-(α-methylbenzyl)-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol)α-methylbenzyl isocyanate, 24.0 mg (97%) of the title compound wererecovered.

MS(m/e): 377(M⁺)

EXAMPLE 75N-(β-(ethoxycarbonyl)phenethyl)-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 16.6 mg (0.0852 mMol)ethyl 2-isocyanato-3-phenylpropionate , 28.0 mg (95%) of the titlecompound were recovered.

MS(m/e): 449(M⁺)

The compounds of Examples 76-79 were prepared at about 50° C. by theprocedure described in detail in Example 42.

EXAMPLE 76N,N-dimethyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 13.0 mg (0.056 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 6.4 mg (0.059 mMol)dimethyl carbamoyl chloride, 13.2 mg (79%) of the title compound wererecovered.

MS(m/e): 301(M⁺)

EXAMPLE 77 N,N-diethyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 13.0 mg (0.056 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 8.0 mg (0.062 mMol)diethyl carbamoyl chloride, 16.05 mg (86%) of the title compound wererecovered.

MS(m/e): 329(M⁺)

EXAMPLE 78N-methyl-N-phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea

Beginning with 13.0 mg (0.056 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 10.1 mg (0.059 mMol)N-methyl-N-phenyl carbamoyl chloride, 17.4 (86%) of the title compoundwere recovered.

MS(m/e): 363(M⁺)

EXAMPLE 795-(morpholin-1-yl)carbonylamino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13.0 mg (0.056 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 8.9 mg (0.059 mMol)morpholine-1-carbonyl chloride, 16.2 (85%) of the title compound wererecovered.

MS(m/e): 343(M⁺)

The compounds of Examples 80-86 were prepared by the procedure describedin detail in Example 53.

EXAMPLE 80N-methyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)thiourea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.56 mg (0.098 mMol)methyl isothiocyanate, 17.0 mg (86%) of the title compound wererecovered.

MS(m/e): 303(M⁺)

EXAMPLE 81N-phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)thiourea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 13.26 mg (0.098 mMol)phenyl isothiocyanate, 16.8 mg (71%) of the title compound wererecovered.

MS(m/e): 365(M⁺)

EXAMPLE 82N-(4-methoxy)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)thiourea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 16.21 mg (0.098 mMol)4-methoxyphenyl isothiocyanate, 18.4 mg (71%;) of the title compoundwere recovered.

MS(m/e): 395(M⁺)

EXAMPLE 83N-(3-trifluoromethyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)thiourea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 19.94 mg (0.098 mMol)3-trifluoromethylphenyl isothiocyanate, 15.6 mg (55%) of the titlecompound were recovered.

MS(m/e): 433(M⁺)

EXAMPLE 84N-(2-phenyl)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)thiourea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 20.73 mg (0.098 mMol)2-biphenyl isothiocyanate, 21.2 mg (74%) of the title compound wererecovered.

MS(m/e): 441(M⁺)

EXAMPLE 85N-(2,3-dichloro)phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)thiourea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 20.04 rag (0.098 mMol)2,3-dichlorophenyl isothiocyanate, 17.7 mg (62%) of the title compoundwere recovered.

MS(m/e): 433(M⁺)

EXAMPLE 86N-benzyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)thiourea

Beginning with 15.0 mg (0.0655 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 14.63 mg (0.098 mMol)benzyl isothiocyanate, 17.0 mg (86%) of the title compound wererecovered.

MS(m/e): 379(M⁺)

EXAMPLE 87 5-phthalimido-3-(1-methylpiperidin-4-yl)-1H-indole oxalate

To a solution of 0.458 gm (2.0 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 8.0 mL dichloromethanewere added 0.438 gm (2.0 mMol) N-carbethoxyphthalimide. The reactionmixture was stirred 18 hours at ambient temperature, at which time thesolvent was removed under reduced pressure. The residue was subjected toflash chromatography, eluting with 100:20:0.5dichloromethane:methanol:ammonium hydroxide, giving 0.467 gm (65%) of5-phthalimido-3-(1-methylpiperidin-4-yl)-1H-indole as a yellow foam. Theyellow foam was dissolved in a mixture of methanol:ethyl acetate and toit was added an equivalent of oxalic acid. The colorless precipitatewhich formed was recrystallized from methanol to give 0.267 gm of thetitle compound as colorless crystals.

m.p.=224° C.; MS(m/e): 359(M⁺) Calculated for C₂₂ H₂₁ N₃ O₂.C₂ H₂ O₄ :Theory: C, 64.13; H, 5.16; N, 9.35. Found: C, 63.88; H, 5.27; 14, 9.51.

EXAMPLE 885-(acetyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

To a solution of 1.0 gm (4.4 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 60 mLtetrahydrofuran were added 0.67 mL (4.8 mMol) triethylamine and thesolution was cooled to 0° C. To this solution were then added 0.32 mL(4.6 mMol) acetyl chloride and the reaction mixture was stirred atambient temperature for 18 hours. The reaction mixture was filtered andconcentrated under reduced pressure to give a dark oil. The oil wastreated with water to give a black gum. This residue was purified byradial chromatography (2 mm, silica), eluting with 100:10:1dichloromethane:methanol:ammonium hydroxide, to give 0.20 gm (16.9%) ofthe title compound as a yellow solid.

m.p.=186-189° C.; MS(m/e): 269(M⁺) Calculated for C₁₆ H₁₉ N₃ O: Theory:C, 71.35; H, 7.11; N, 15.60. Found: C, 71.18; H, 6.97; N, 15.46.

The compounds of Examples 89-110 are prepared by the procedure describedin detail in Example 88.

EXAMPLE 895-(propanoyl)amino-3-(1-methyl-1,2,3,6-tetralhydropyridin-4-yl)-1H-indolefumarate

Beginning with 1.0 gm (4.4 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.74mL (5.3 mMol) propanoyl chloride, 0.287 gm (23%) of the title compoundwere recovered as a red powder.

m.p.=170-173° C.; MS(m/e): 283(M⁺) Calculated for C₁₇ H₂₁ N₃ O.C₄ H₄ O₄: Theory: C, 63.15; H, 6.31; N, 10.52. Found: C, 62.97; H, 6.04; N,10.66.

EXAMPLE 905-(benzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.13 gm (5.0 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.58mL (5.0 mMol) benzoyl chloride, 0.477 gm (28.9%) of the title compoundwere recovered as a light green solid.

m.p.>250° C.; MS(m/e): 331(M⁺) Calculated for C₂₁ H₂₁ N₃ O: Theory: C,76.11; H, 6.39; N, 12.68. Found: C, 75.84; H, 6.22; N, 12.41.

EXAMPLE 915-(4-chlorobenzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.13 gm (5.0 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.64mL (5.0 mMol) 4-chlorobenzoyl chloride, 0.544 gm (29.9%) of the titlecompound were recovered as a tan solid.

m.p.=224-226° C.; MS(m/e): 365(M⁺) Calculated for C₂₁ H₂₀ N₃ OCl:Theory: C, 68.94; H, 5.51; N, 11.48. Found: C, 68.75; H, 5.65; N, 11.63.

EXAMPLE 925-(4-methoxybenzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.13 gm (5.0 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.853gm (5.0 mMol) 4-methoxybenzoyl chloride, 0.367 gm (20.4%) of the titlecompound were recovered as a light yellow solid.

m.p.=232° C. (dec.); MS(m/e): 361(M⁺) Calculated for C₂₂ H₂₃ N₃ O₂ :Theory: C, 73.:11; H, 6.41; N, 11.63. Found: C, 72.86; H, 6.39; N,11.33.

EXAMPLE 935-(2-chloro-4-fluorobenzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 2.0 gm (8.8 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 1.9 gm(9.7 mMol) 2-chloro-4-fluorobenzoyl chloride, 0.67 gm (19.8%) of thetitle compound were recovered as a light: yellow solid.

m.p.=212-222° C.; MS(m/e): 383(M⁺) Calculated for C₂₁ H₁₉ N₃ OClF:Theory: C, 65.71; H, 4.99; N, 10.95. Found: C, 66.00; H, 5.10; N, 10.84.

EXAMPLE 945-(4-fluorobenzoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 2.69 gm (11.1 mMol)5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 1.45 mL(12.3 mMol) 4-fluorobenzoyl chloride, 2.39 gm (59.0%) of the titlecompound were recovered as a burnt orange powder.

m.p.=127-135° C. (dec.); MS(m/e): 363(M⁺) Calculated for C₂₂ H₂₂ N₃ OF:Theory: C, 72.71; H, 6.10; N, 11.56. Found: C, 72.42; H, 6.14; N, 11.33.

EXAMPLE 955-(2-furoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.13 gm (5.0 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.52mL (5.0 mMol) 2-furoyl chloride, 0.129 gm (8.1%) of the title compoundwere recovered as a tan solid.

m.p.=190° C. (dec.); MS(m/e): 321(M⁺) Calculated for C₁₉ H₁₉ N₃ O₂ :Theory: C, 71.01; H, 5.96; N, 13.08. Found: C, 71.26; H, 6.17; N, 12.85.

EXAMPLE 965-(2-thienoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Beginning with 1.0 gm (4.4 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.494mL (4.6 mMol) 2-thiophenecarbonyl chloride, 0.489 gm (33.0%) of thetitle compound were recovered as a bright yellow solid.

m.p.=229-233° C. (dec.); MS(m/e): 337(M⁺) Calculated for C₁₉ H₁₉ N₃ OS:Theory: C, 67.63; H, 5.67; N, 12.45. Found: C, 67.44; H, 5.70; N, 12.22.

EXAMPLE 97 5-(acetyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 2.00 gm (5.74 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole dihydrochloride ethanolateand 1.13 gm (25.8 mMol) acetyl chloride, 1.22 gm (78.3%) of the titlecompound were recovered as a white powder.

m.p.=161-165° C. (dec.); MS(m/e): 271(M⁺) Calculated for C₁₆ H₂₁ N₃ O:Theory: C, 70.82; H, 7.80; N, 15.48. Found: C, 70.52; H, 7.83; N, 15.37.

EXAMPLE 98 5-(propanoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indolefumarate

Beginning with 0.945 gm (4.12 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 0.689 mL, (4.94 mMol)propanoyl chloride, 1.3 gm (81.2%) of the title compound were recoveredas a tan solid.

m.p.=88-92° C. (dec.); MS(m/e): 285(M⁺) Calculated for C₁₇ H₂₃ N₃ O.C₄H₄ O₄ : Theory: C, 62.83; H, 6.78; N, 10.47. Found: C, 62.61; H, 6.84;N, 10.25.

EXAMPLE 99 5-(trimethylacetyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 2.00 gm (5.74 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole dihydrochloride ethanolateand 1.78 gm (14.4 mMol) trimethylacetyl chloride, 0.623 gm (34.6%) ofthe title compound were recovered as an off-white powder.

m.p.=214-216° C. (dec.); MS(m/e): 313(M⁺) Calculated for C₁₉ H₂₇ N₃ O:Theory: C, 72.81; H, 8.68; N, 13.41. Found: C, 72.56; H, 8.73; N, 13.28.

EXAMPLE 100 5-(benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indoleoxalate

Beginning with 0.545 gm (2.4 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 0.398 mL (2.85 mMol)benzoyl chloride, 0.92 gm (90.5%) of the title compound were recoveredas an off-white solid.

m.p.=130° C.; MS(m/e): 333(M⁺) Calculated for C₂₁ H₂₃ N₃ O.C₂ H₂ O₄ :Theory: C, 65.24; H, 5.95; N, 9.92. Found: C, 64.98; H, 6.12; N, 9.84.

EXAMPLE 1015-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

Beginning with 15.2 gm (66 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 7.8 mL (66 mMol)4-fluorobenzoyl chloride, 13.01 gm (42.2%) of the title compound wererecovered as an off-white solid.

m.p.=139-140° C. (dec.); MS(m/e): 351(M⁺) Calculated for C₂₁ H₂₂ N₃OF.C₄ H₄ O₄ : Theory: C, 64.23; H, 5.61; N, 8.99. Found: C, 63.96; H,5.65; N. 9.05.

EXAMPLE 1025-(2-chlorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

Beginning with 1.14 gm (5.0 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 0.63 mL (5.0 mMol)2-chlorobenzoyl chloride, 0.406 gm (16.8%) of the title compound wererecovered as colorless crystals.

m.p.=209° C. (dec.); MS(m/e): 367(M⁺) Exact Mass: Theory: 368.1530.Found: 368.1531.

EXAMPLE 1035-(3-chlorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

Beginning with 1.14 gm (5.0 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 0.62 mL (5.0 mMol)3-chlorobenzoyl chloride, 0.942 gm (38.9%) of the title compound wererecovered as a colorless solid.

m.p.=185° C. (dec.); MS(m/e): 367(M⁺) Calculated for C₂₁ H₂₂ N₃ OCl.C₄H₄ O₄ : Theory: C, 62.05; H, 5.41; N, 8.68. Found: C, 61.77; H, 5.60; N,8.61.

EXAMPLE 1045-(4-chlorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

Beginning with 1.14 gm (5.0 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 0.64 mL (5.0 mMol)4-chlorobenzoyl chloride, 0.339 gm (14.0%) of the title compound wererecovered as a colorless solid.

m.p.=163° C. (dec.); MS(m/e): 367(M⁺) Calculated for C₂₁ H₂₂ N₃ OCl.C₄H₄ O₄ : Theory: C, 62.05; H, 5.42; N, 8.68. Found: C, 61.92; H, 5.47; N,8.52.

EXAMPLE 1055-(2-methoxybenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

Beginning with 1.14 gm (5.0 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 0.74 mL (5.0 mMol)2-methoxybenzoyl chloride, 0.569 gm (23.7%) of the title compound wererecovered as an off-white solid.

m.p.=90° C. (dec.); MS(m/e): 364(M⁺) Exact Mass: Theory: 364.2025.Found: 364.2029.

EXAMPLE 1065-(3-methoxybenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

Beginning with 1.14 gm (5.0 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 0.70 mL (5.0 mMol)3-methoxybenzoyl chloride, 0.653 gm (27.2%) of the title compound wererecovered as an off-white solid.

m.p.=152° C. (dec.); MS(m/e): 364(M⁺) Calculated for C₂₂ H₂₅ N₃ O₂.C₄ H₄O₄ : Theory: C, 65.12; H, 6.10; N, 8.76. Found: C, 64.85; H, 6.38; N,8.48.

EXAMPLE 1075-(4-methoxybenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

Beginning with 1.14 gm (5.0 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 0.853 gm (5.0 mMol)4-methoxybenzoyl chloride, 0.398 gm (16.6%) of the title compound wererecovered as an off-white solid.

m.p.=151° C. (dec.); MS(m/e): 364(M⁺) Exact Mass: Theory: 364.2025.Found: 364.2032.

EXAMPLE 108 5-(2-furoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indolefumarate

Beginning with 1.14 gm (5.0 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 0.52 mL (5.0 mMol)2-furoyl chloride, 0.420 gm (19.1%) of the title compound were recoveredas an off-white solid.

m.p.=114° C. (dec.); MS(m/e): 324(M⁺) Calculated for C₁₉ H₂₁ N₃ O₂.C₄ H₄O₄ : Theory: C, 62.86; H, 5.73; N, 9.56. Found: C, 63.15; H, 5.89; M,9.84.

EXAMPLE 109 5-(2-thienoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indoleoxalate

Beginning with 0.72 gm (3.14 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 0.525 mL (3.8 mMol)2-thienoyl chloride, 1.2 gm of the title compound were recovered as anoff-white solid.

m.p.=135° C. (dec.); MS(m/e): 339(M⁺) Calculated for C₁₉ H₂₁ N₃ OS.C₂ H₂O₄ : Theory: C, 58.61; H, 5.54; N, 9.64. Found: C, 58.90; H, 5.41; N,9.89.

EXAMPLE 110 5-(phenylacetyl)amino-3-(1-methylpiperidin-41-yl)-1H-indoleoxalate

Beginning with 2.00 gm (5.74 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole dihydrochloride ethanolateand 2.23 gm (14.4 mMol) phenylacetyl chloride, 0.80 gm of the titlecompound were recovered as a tan solid.

m.p.<90° C.; MS(m/e): 347(M⁺) Calculated for C₂₂ H₂₅ N₃ O.C₂ H₂ O₄ :Theory: C, 65.89; H, 6.22; N, 9.60. Found: C, 65.68; H, 6.29; N, 9.83.

EXAMPLE 1115-(fur-2-oyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

A. Preparation of 5-(2-furoyl)amino-1H-indole

To a solution of 2.09 gm (15.8 mMol) 5-amino-1H-indole in 20 mLtetrahydrofuran were added 2.6 mL (18.97 mMol) triethylamine and thesolution was cooled in an ice bath. To the reaction mixture were thenadded dropwise 1.71 ml (17.4 mMol) 2-furoyl chloride. When this additionwas complete the cooling bath was removed and the reaction mixture wasstirred 1.5 hours at ambient temperature. At this point the reaction wasdiluted with water and extracted well with ethyl acetate. The organicsolutions were combined and washed sequentially with water, 2N sodiumhydroxide, water and saturated aqueous sodium chloride. The remainingorganics were then dried over sodium sulfate and concentrated underreduced pressure to give a dark purple solid. The solid was subjected toflash chromatography, eluting with a gradient of dichloromethanecontaining 0-2% methanol. The recovered solid was crystallized fromethyl acetate to give 1.8 gm (50.3%) of 5-(2-furoyl)amino-1H-indole aspale purple crystals.

m.p.=181-182° C.; MS(m/e): 227(M+1) Calculated for C₁₃ H₁₀ N₂ O₂ :Theory: C, 69.02; H, 4.46; N, 12.38. Found: C, 68.79; H, 4.52; N, 12.25.

B. Condensation of substituted indole with 1-ethyl-4-piperidone

To a solution of 0.868 gm (15.5 mMol) potassium hydroxide in 8 mLmethanol were added 1.0 gm (4.42 mMol) 5-(2-furoyl)amino-1H-indole and0.774 mL 1-ethyl-4-piperidone and the solution was stirred at reflux for18 hours. The reaction mixture was cooled to ambient and then dilutedwith ice/water. The resultant precipitate was collected and dried undervacuum. This solid was purified by radial chromatography (2 mm silica),eluting with a gradient of dichloromethane containing 5-7.5% methanoland 0.5-1.0% ammonium hydroxide. The product was then crystallized fromethyl acetate to give 0.715 gm (48.3%) of the title compound as a brightyellow powder.

m.p.=120-122° C.; MS(m/e): 336(M+1) Calculated for C₂₀ H₂₁ N₃ O₂ :Theory: C, 71.62; H, 6.31; N, 12.53. Found: C, 71.51; H, 6.33; N, 12.73.

EXAMPLE 112 5-(2-furoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indole

To a solution of 0.780 gm (3.2 mMol)5-amino-3-(1-ethylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuran and10 mL dimethylformamide were added 0.536 mL (3.85 mMol) triethylaminefollowed by the dropwise addition of 0.348 mL (3.5 mMol) 2-furoylchloride. After 18 hours the reaction mixture was cooled in an ice bath.The reaction mixture was the partitioned between 100 mL ethyl acetateand 100 mL 2N sodium hydroxide. The phases were separated and theaqueous extracted again with ethyl acetate. Organic extracts werecombined and washed sequentially with 2N sodium hydroxide, water andsaturated aqueous sodium chloride. The remaining organics were driedover sodium sulfate and concentrated under reduced pressure. The residuewas subjected to radial chromatography (2 mm silica), eluting with100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractionscontaining product were combined and concentrated under reducedpressure. The residue was crystallized from ethyl acetate/hexane to give0.789 gm (73.1%) of the title compound as an off-white solid.

m.p.=178-179° C.; MS(m/e): 338(M+1) Calculated for C₂₀ H₂₃ N₃ O₂ :Theory: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.44; H, 7.09; N, 12.40.

EXAMPLE 113 5-(4-fluorobenzoyl)amino-3-(1-ethylpiperidin-4-yl)-1H-indolefumarate

Following the procedure described in detail in Example 32, 1.14 gm (3.14mMol)5-(4-fluorobenzoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolewere hydrogenated to give 0.527 gm (34.8%) of the title compound as atan powder.

m.p.=152-155° C.; MS(m/e): 366(M+1) Calculated for C₂₂ H₂₄ N₃ OF.C₄ H₄O₄ : Theory: C, 64.85; H, 5.86; N, 8.73. Found: C, 65.15; H, 5.95; N,8.95.

EXAMPLE 1145-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

To a solution of 0.40 gm (1.04 mMol)5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolein 5.2 mL trifluoroacetic acid were added 0.208 mL (1.3 mMol)triethylsilane and the reaction mixture was stirred at ambient. After 2hours, the reaction mixture was concentrated under reduced pressure. Tothe residue was added 2N sodium hydroxide and the aqueous was extractedwith dichloromethane. The combined organic extracts were washed with 2Nsodium hydroxide, dried over sodium sulfate and then concentrated underreduced pressure to give an orange foam. The foam was subjected toradial chromatography (2 mm silica), eluting with 100:10:1dichloromethane:methanol:ammonium hydroxide. The residue wascrystallized from ethyl acetate/hexanes to give 0.27 gm (67.3%) of thetitle compound as a burnt orange powder.

MS(m/e): 385(M⁺);

The compounds of Examples 115-124 were prepared by the proceduredescribed in detail in Example 42.

EXAMPLE 115 5-(methoxyacetyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.056 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 6.5 mg (0.059 mMol)methoxy-acetyl chloride, 14.2 mg (84%) of the title compound wererecovered.

MS(m/e): 302(M⁺)

EXAMPLE 1165-((2-thienyl)acetyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.056 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.6 mg (0.059 mMol)(2-thiophene)acetyl chloride, 14.1 mg (72%) of the title compound wererecovered.

MS(m/e): 354(M⁺)

EXAMPLE 1175-(3-(methoxycarbonyl)propanoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.056 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.0 mg (0.059 mMol)(3-methoxy-carbonyl)propanoyl chloride, 14.1 mg (75%) of the titlecompound were recovered.

MS(m/e): 344(M⁺)

EXAMPLE 1185-(2-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 5.4 μL (0.0458 mMol)2-fluorobenzoyl chloride, 12.2 mg (80%) of the title compound wererecovered.

MS(m/e): 351(M⁺)

EXAMPLE 1195-(2-methylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 6.0 μL (0.0458 mMol)2-methylbenzoyl chloride, 14.3 mg (95%) of the title compound wererecovered.

MS(m/e): 348(M+1)

EXAMPLE 1205-(3-methylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.056 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.2 mg (0.059 mMol)3-methylbenzoyl chloride, 17.1 mg (88%) of the title compound wererecovered.

MS(m/e): 348(M⁺)

EXAMPLE 1215-(2-trifluoromethylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.056 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 13.0 mg (0.062 mMol)2-trifluoromethylbenzoyl chloride, 20.3 mg (89%) of the title compoundwere recovered.

MS(m/e): 401(M⁺)

EXAMPLE 1225-(3,4-dichlorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.6 mg (0.0458 mMol)3,4-dichlorobenzoyl chloride, 14.4 mg (82%) of the title compound wererecovered.

MS(m/e): 401(M⁺)

EXAMPLE 1235-(2,4-dichlorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10 mg (0.0437 mMol)5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 6.4 μL (0.0458 mMol)2,4-dichlorobenzoyl chloride, 12.2 mg (80%) of the title compound wererecovered.

MS(m/e): 401(M⁺)

EXAMPLE 124 5-(isoxazol-5-oyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 13 mg (0.056 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 8.21 mg (0.062 mMol)isoxazole-5-carbonyl chloride, 10.4 mg (57%) of the title compound wererecovered.

MS(m/e): 325(M⁺)

EXAMPLE 125 Alternate Synthesis of5-(2-thienoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole oxalate

To a solution of 0.615 gm (4.8 mMol) 2-1thienoic acid in 10 mLdichloromethane were added 0.778 gm (4.8 mMol) N,N-carbonyldiimidazolein 2 mL dichloromethane. After 1.5 hour, a solution of 1.0 gm (4.4 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 15 mL dichlioromethanewas added and the reaction mixture stirred for 18 hours at ambient. Thereaction mixture was washed sequentially with 1N sodium hydroxide, waterand saturated aqueous sodium chloride. The remaining organics were driedover sodium sulfate and the volatiles removed under reduced pressure.The residual brown foam was subjected to radial chromatography (2 mmsilica), eluting with a gradient of dichloromethane containing 5-7.5%methanol and 0.5% ammonium hydroxide. Fractions shown to contain productwere combined and concentrated under reduced pressure. This material wasdissolved in ethyl acetate/ethanol and was treated with oxalic acid togive 0.20 gm (10.7%) of the title compound as a tan solid.

m.p.=160° C.; MS(m/e): 339(M⁺) Calculated for C₁₉ H₂₁ N₃ OS.C₂ H₂ O₄ :Theory: C, 58.73; H, 5.40; N, 9.78. Found: C, 58.61; H, 5.54; N, 9.64.

General Procedure for the Coupling of Carboxilic Acids with5-amino-3-(1-methylpiperidin-4-yl)-1H-indole

To a suspension of 4-5 equivalents of polymer bound1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (Desai, et al.,Tetrahedron Letters, 34(48), 7685 (1993)) in chloroform are added 1equivalent of 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 2-3equivalents of the carboxylic acid. The reaction is agitated until thereaction is complete, heat may be applied if necessary. The resin isremoved by filtration and the product isolated by evaporation ofsolvent. This procedure is illustrated by Examples 126-178.

EXAMPLE 126 5-(1-propanoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 8 μL (0.1 mMol)1-propanoic acid, 13.0 mg (91%) of the title compound were recovered.

MS(m/e): 286(M+1)

EXAMPLE 1275-(2-methylpropanoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 8.8 mg (0.10 mMol)isobutyric acid, 11.8 mg (79%) of the title compound were recovered.

MS(m/e): 300(M+1)

EXAMPLE 1285-(3-methylbutanoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 10.0 mg (0.10 mMol)isovaleric acid, 17.0 mg (100+%) of the title compound were recovered.

MS(m/e): 314(M⁺)

EXAMPLE 129 5-(1-pentanoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 10.0 mg (0.10 mMol)pentanoic acid, 12.8 mg (82%) of the title compound were recovered.

MS(m/e): 314(M+1)

EXAMPLE 130 5-(ethoxyacetyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.0 μL (0.10 mMol)ethoxyacetic acid, 15.2 mg (97%) of the title compound were recovered.

MS(m/e): 316(M+1)

EXAMPLE 131 5-(phenoxyacetyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.10 mMol)phenxoyacetic acid, 9.4 mg (52%) of the title compound were recovered.

MS(m/e): 364(M+1)

EXAMPLE 132 5-(diphenylacetyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.10 mMol)diphenylacetic acid, 14.0 mg (66%) of the title compound were recovered.

MS(m/e). 424(M+1)

EXAMPLE 133 5-(cinnamoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.10 mMol)cinnamic acid, 7.2 mg (40%) of the title compound were recovered.

MS(m/e) 360(M+1)

EXAMPLE 1345-(cyclopropanecarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.0 μL (0.10 mMol)cyclopropanecarboxylic acid, 11.4 mg (77%) of the title compound wererecovered.

MS(m/e): 298(M+1)

EXAMPLE 1355-(cyclobutanecarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.10 mMol)cyclobutanecarboxylic acid, 15.0 mg (96%) of the title compound wererecovered.

MS(m/e): 312(M+1)

EXAMPLE 1365-(cyclopentanecarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.0 mg (0.10 mMol)cyclopentanecarboxylic acid, 16.4 mg (100+%) of the title compound wererecovered.

MS(m/e): 326(M+1)

EXAMPLE 1375-(cyclohexanecarbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 13.0 mg (0.10 mMol)cyclohexanecarboxylic acid, 20.6 mg (100+%) of the title compound wererecovered.

MS(m/e): 340(M+1)

EXAMPLE 1385-(1,2,3,4-tetrahydronaphth-1-oyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 16.2 mg (0.10 mMol)1,2,3,4-tetrahydro-1-naphthoic acid at 70° C., 16.2 mg (84%) of thetitle compound were recovered.

MS(m/e): 388(M+1)

EXAMPLE 1395-(3-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.15 mMol)3-fluorobenzoic acid, 11.8 mg (67%) of the title compound wererecovered.

MS(m/e): 352(M+1)

EXAMPLE 140 5-(4-bromobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 20.0 mg (0.087 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 52.0 mg (0.131 mMol)4-bromobenzoic acid, 27.3 mg (75.8%) of the title compound wererecovered.

MS(m/e): 413(M⁺)

EXAMPLE 141 5-(4-iodobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32.0 mg (0.131 mMol)4-iodobenzoic acid, 12.0 mg (60%) of the title compound were recovered.

MS(m/e): 459(M⁺)

EXAMPLE 142 5-(3-iodobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32.0 mg (0.131 mMol)3-iodobenzoic acid, 15.9 mg (80%) of the title compound were recovered.

MS(m/e): 459(M⁺)

EXAMPLE 1435-(4-methylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Reacting 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 14.0 mg (0.10 mMol)4-methylbenzoic acid at 70° C., 12.0 mg (69%) of the title compound wererecovered.

MS(m/e): 348(M+1)

EXAMPLE 1445-(4-hexyloxybenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 30.0 mg (0.131 mMol)4-hexyloxybenzoic acid, 16.8 mg (89%) of the title compound wererecovered.

MS(m/e): 434(M+1)

EXAMPLE 1455-(4-trifluoromethylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 29.0 mg (0.15 mMol)4-trifluoromethylbenzoic acid, 11.6 mg (58%) of the title compound wererecovered.

MS(m/e): 402(M+1)

EXAMPLE 1465-(3-trifluoromethylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.1 mg (0.09 mMol)3-trifluoromethylbenzoic acid, 8.7 mg (72%) of the title compound wererecovered.

MS(m/e): 403(M+2)

EXAMPLE 147 5-(4-cyanobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 20.0 mg (0.087 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 38.0 mg (0.131 mMol)4-cyanobenzoic acid, 13.5 mg (43.1%) of the title compound wererecovered.

MS(m/e): 359(M+1)

EXAMPLE 148 5-(4-nitrobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 20.0 mg (0.087 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol)4-nitrobenzoic acid, 13.8 mg (41.8%) of the title compound wererecovered.

MS(m/e): 379(M+1)

EXAMPLE 1495-(4-(methylthio)benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 20.0 mg (0.087 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol)4-(methylthio)benzoic acid, 18.9 mg (57.1%) of the title compound wererecovered.

MS(m/e): 380(M+1)

EXAMPLE 1505-(3-(dimethylamino)benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Reacting 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 17.0 mg (0.10 mMol)3-(dimethylamino)benzoic acid at 70° C., 12.4 mg (66%) of the titlecompound were recovered.

MS(m/e): 377(M+1)

EXAMPLE 1515-(4-phenylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Reacting 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 20.0 mg (0.10 mMol)4-phenylbenzoic acid at 70° C., 10.0 mg (49%) of the title compound wererecovered.

MS(m/e): 410(M+1)

EXAMPLE 1525-(4-(acetyl)benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 20.0 mg (0.087 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol)4-(acetyl)benzoic acid, 16.5 mg (50.5%) of the title compound wererecovered.

MS(m/e): 376(M+1)

EXAMPLE 1535-(4-(benzoyl)benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 30.0 mg (0.131 mMol)4-(benzoyl)benzoic acid, 14.4 mg (75%) of the title compound wererecovered.

MS(m/e): 438(M+1)

EXAMPLE 1545-(4-(methanesulfonyl)benzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 18.0 mg (0.09 mMol)4-(methanesulfonyl)benzoic acid, 7.2 mg of the title compound wererecovered.

MS(m/e): 411(M⁺)

EXAMPLE 1555-(3,5-dichlorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.2 mg (0.09 mMol)3,5-dichlorobenzoic acid, 10.3 mg of the title compound were recovered.

MS(m/e): 402(M⁺)

EXAMPLE 1565-(3,4-dimethylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.6 mg (0.131 mMol)3,4-dimethylbenzoic acid, 12.0 mg (76%) of the title compound wererecovered.

MS(m/e): 362(M+1)

EXAMPLE 1575-(3,5-dimethylbenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.6 mg (0.131 mMol)3,5-dimethylbenzoic acid, 15.0 mg (95%) of the title compound wererecovered.

MS(m/e): 362(M+1)

EXAMPLE 1585-(2,3-dimethoxybenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 16.4 mg (0.09 mMol)2,3-dimethoxybenzoic acid, 11.4 mg (97%) of the title compound wererecovered.

MS(m/e): 394(M+1)

EXAMPLE 1595-(3-nitro-4-chlorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 26.4 mg (0.131 mMol)3-nitro-4-chlorobenzoic acid, 11.4 mg (63.3%) of the title compound wererecovered.

MS(m/e): 412(M⁺)

EXAMPLE 1605-(3,4,5-trimethoxybenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 27.8 mg (0.131 mMol)3,4,5-trimethoxybenzoic acid, 13.8 mg (75%) of the title compound wererecovered.

MS(m/e): 424(M+1)

EXAMPLE 1615-(3,5-(di-t-butyl)-4-hydroxybenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32.8 mg (0.131 mMol)3,5-di(t-butyl)-4-hydroxybenzoic acid, 15.0 mg (75%) of the titlecompound were recovered.

MS(m/e): 462(M+1)

EXAMPLE 1625-(pyridine-2-carbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.0 mg (0.15 mMol)pyridine-2-carboxylic acid, 14.2 mg (85%) of the title compound wererecovered.

MS(m/e): 335(M+1)

EXAMPLE 1635-(pyridine-3-carbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.09 mMol)pyridine-3-carboxylic acid, 7.4 mg of the title compound were recovered.

MS(m/e): 335(M+1)

EXAMPLE 1645-(pyridine-4-carbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.09 mMol)pyridine-4-carboxylic acid, 7.0 mg of the title compound were recovered.

MS(m/e): 335(M+1)

EXAMPLE 1655-(6-chloropyridine-3-carbonyl)amino-3-l(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 14.2 mg (0.09 mMol)6-chloropyridine-3-carboxylic acid, 4.4 mg (40%) of the title compoundwere recovered.

MS(m/e): 369(M+1)

EXAMPLE 166 5-(2-quinolinoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.0 mg (0.10 mMol)2-quinaldic acid, 17.6 mg (92%) of the title compound were recovered.

MS(m/e): 385(M+1)

EXAMPLE 1675-(pyrazine-2-carbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 20.0 mg (0.087 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32 mg (0.131 mMol)pyrazine-2-carboxylic acid, 6.9 mg (24%) of the title compound wererecovered.

MS(m/e): 336(M+1)

EXAMPLE 168 5-(2-pyrroyl )amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.1 mg (0.131 mMol)pyrrole-2-carboxylic acid, 12.6 mg (78%) of the title compound wererecovered.

MS (m/e) 323(M+1)

EXAMPLE 1695-(N-methyl-2-pyrroyl)amino-3-((1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.0 mg (0.15 mMol)N-methylpyrrole-2-carboxylic acid, 13.0 mg (85+%) of thee title compoundwere recovered.

MS(m/e): 337(M+1)

EXAMPLE 1705-(2-methyl-3-furoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.3 mg (0.09 mMol)2-methyl-3-furoic acid, 0.4 mg (4%) of the title compound wererecovered.

MS(m/e): 338(M+1)

EXAMPLE 171 5-(3-furoyl )amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.0 mg (0.15 mMol)3-furoic acid, 13.8 mg (35%) of the title compound were recovered.

MS(m/e): 324(M+1)

EXAMPLE 1725-(5-methyl-2-furoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.3 mg (0.09 mMol)5-methyl-2-furoic acid, 1.5 mg (87%) of the title compound wererecovered.

MS(m/e): 338(M+1)

EXAMPLE 1735-(5-bromo-2-furoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 10.0 mg (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 25.0 mg (0.131 mMol)5-brono-2-furoic acid, 8.4 mg (49%) of the title compound wererecovered.

MS(m/e): 403(M⁺)

EXAMPLE 1745-(benzofuran-2-carbonyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 24.0 mg (0.15 mMol)benzofuran-2-carboxylic acid, 15.6 mg (84%) of the title compound wererecovered.

MS(m/e): 3 74(M+1)

EXAMPLE 175 5-(3-thienoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.5 mg (0.09 mMol)3-thienoic acid, 9.4 mg (92%) of the title compound were recovered.

MS(m/e): 340(M+1)

EXAMPLE 1765-(3-methyl-2-thienoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 12.8 mg (0.09 mMol)3-methyl-2-thienoic acid, 9.6 mg (90%) of the title compound wererecovered.

MS(m/e): 354(M+1)

EXAMPLE 1775-(5-methyl-2-thienoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 12.0 mg (0.05 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.10 mMol)5-methyl-2-thienoic acid, 13.0 mg (74%) of the title compound wererecovered.

MS(m/e): 354(M+1)

EXAMPLE 1785-(4-methoxy-3-thienoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

Beginning with 7.0 mg (0.03 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 14.2 mg (0.09 mMol)4-methoxy-3-thienoic acid, 12.1 mg of the title compound were recovered.

MS(m/e): 369(M⁺).

EXAMPLE 179 5-(1-naphthoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indolehydrochloride

To a suspension of 1.2 gm (5.2 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 50 mL tetrahydrofuranwere added 0.946 mL (6.3 mMol) 1-naphthoyl chloride dropwise. After 18hours the reaction mixture was filtered. The recovered filtrate wasdissolved in 10 mL dimethylformamide to which were added 1.5 mL (10.5mMol) triethylamine followed by 0.8 mL (5.3 mMol) 1-naphthoyl chloride.After 18 hours the reaction mixture was partitioned between ethylacetate and 1N sodium hydroxide. The phases were separated and theaqueous extracted again with ethyl acetate. The combined ethyl acetateextracts were then washed sequentially with 1N sodium hydroxide, waterand saturated aqueous sodium chloride. The remaining organics were driedover sodium sulfate and concentrated under reduced pressure. The residuewas subjected to flash chromatography, eluting with 100:10:1dichloromethane:methanol:ammonium hydroxide. Fractions shown to containproduct were combined and concentrated under reduced pressure. Theresidue was taken up in ethanol and treated with ethanolic hydrogenchloride. The solution was concentrated under reduced pressure and theresidue crystallized from ethylacetate/ethanol to give 1.28 gm (58.2%)of the title compound as a tan powder.

m.p.=193-203° C.; MS(m/e): 384(M+1) Calculated for C₂₅ H₂₅ N₃ O.HCl.0.3CH₃ CO₂ CH₂ CH₃ : Theory: C, 70.50; H, 6.41; N, 9.41; Cl, 7.94. Found:C, 70.10; H, 6.41; N, 9.41; Cl, 8.34.

EXAMPLE 180 5-(2-naphthoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

To a solution of 0.989 gm (4.31 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 20 mL tetrahydrofuranand 10 mL dimethylformamide were added 0.721 mL (5.2 mMol) triethylaminefollowed by 0.904 gm (4.74 mMol) 2-naphthoyl chloride. After 18 hoursthe reaction mixture was cooled in an ice bath and then diluted with 100mL ethyl acetate followed by 50 mL 2N sodium hydroxide. The phases wereseparated and the aqueous extracted with ethyl acetate. The organicextracts were combined then washed sequentially with 2N sodiumhydroxide, water and saturated aqueous sodium chloride. The remainingorganics were dried over sodium sulfate and concentrated under reducedpressure. The residue was subjected to flash chromatography, elutingwith 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractionsshown to contain product were combined and concentrated under reducedpressure. The residue was precipitated from ethyl acetate/hexane to give1.355 gm (82.1%) of the title compound as a tan powder.

m.p.=153-155.5° C.; MS(m/e): 383(M⁺) Calculated for C₂₅ H₂₅ N₃ O:Theory: C, 78.30; H, 6.57; N, 10.96. Found: C, 78.24; H, 6.63; N, 11.10.

EXAMPLE 181 Alternate Synthesis of5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole

To a suspension of 0.804 gm (3.5 mMol)5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuranand 5.0 mL dimethylformamide were added 0.536 mL (4.2 mMol)triethylamine followed by a solution of 0.714 gm (3.86 mMol)2-chloro-4-fluorobenzoyl chloride in 5 mL tetrahydrofuran. After 18hours the reaction mixture was diluted with ethyl acetate followed by 2Nsodium hydroxide. The phases were separated and the aqueous extractedwith ethyl acetate. The organic extracts were combined then washedsequentially with 2N sodium hydroxide, water and saturated aqueoussodium chloride. The remaining organics were dried over sodium sulfateand concentrated under reduced pressure. The residue was subjected toflash chromatography, eluting with 100:10:1dichloromethane:methanol:ammonium hydroxide. Fractions shown to containproduct were combined and concentrated under reduced pressure. Theresidue was precipitated from ethyl acetate to give 0.921 gm (68.2%) ofthe title compound as a light pink powder.

m.p.=159-162° C.; MS(m/e): 385(M⁺) Calculated for C₂₁ H₂₁ N₃ OClF:Theory: C, 65.37; H, 5.49; N, 10.89. Found: C, 65.15; H, 5.55; N, 10.74.

EXAMPLE 182 Alternate Synthesis of5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

A. Preparation of 5-(4-fluorobenzoyl)amino-1H-indole

To a solution of 3.96 gm (30.0 mMol) 5-amino-1H-indole in 150 mLtetrahydrofuran were added 5.6 mL triethylamine followed by a solutionof 5.2 gm (33.0 mMol) 4-fluorobenzoyl chloride in 30 mL tetrahydrofuran.After 18 hours the reaction mixture was poured into water, made basicwith sodium hydroxide solution, and extracted with dichloromethane. Theorganic extracts were combined, dried over sodium sulfate andconcentrated under reduced pressure to give a purple solid. This residuewas recrystallized from ethyl acetate/hexane to give 6.37 gm (84%)5-(4-fluoro-benzoyl)amino-1H-indole as brown crystals in two crops.

m.p.=205-207° C.; MS(m/e): 254(m⁺) Calculated for C₁₅ H₁₁ N₂ OF: Theory:C, 70.86; H, 4.36; N, 11.02. Found: C, 70.64; H, 4.43; N, 10.73.

B. Preparation of5-(4-fluorobenzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

A solution of 2.54 gm (10 mMol) 5-(4-fluorobenzoyl)-amino-1H-indole and1.7 gm (15.0 mMol) 1-methyl-4-piperidone in 20 mL 10% methanolicpotassium hydroxide was heated to reflux for 3.5 hours and then allowedto stir without heating. After 18 hours the resultant suspension wasfiltered, the solid washed with methanol and then dried under reducedpressure to give 2.30 gm (65.8%)5-(4-fluorobenzoyl)-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoleas a tan powder.

m.p.=187.5-189.5° C.; MS(m/e): 349(M⁺) Calculated for C₂₁ H₂₀ N₃ OF:Theory: C, 72.19; H, 5.77; N, 12.03. Found: C, 72.36; H, 5.87; N, 12.01.

C. Hydrogenation of5-(4-fluorobenzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

To a solution of 0.84 gm (2.4 mMol)5-(4-fluorobenzoyl)-amino-3-(1-methyl-1,2,3,6-tertrahydropyridin-4-yl)-1H-indolein 100 mL methanol were addled 0.25 gm 5% palladium on carbon and themixture stirred under a hydrogen atmosphere maintained with a hydrogenfilled balloon. After 15 hours the mixture was filtered and the filtrateconcentrated under reduced pressure. The residual light yellow glass wasthen subjected to Florisil™ chromatography, eluting with 4:1dichloromethane:methanol containing a trace of ammonium hydroxide.Fractions shown to contain product were combined and concentrated underreduced pressure. The residue was dissolved in ethyl acetate and thissolution treated with a saturated solution of fumaric acid in methanol.The solvent was decanted from the precipitate which was recrystallizedfrom ethyl acetate/methanol to give 0.377 gm (33.6%) of the titlecompound as colorless needles in two crops.

m.p.=155-158° C. (dec.); MS(m/e): 351(M⁺) Calculated for C₂₁ H₂₂ N₃OF.C₄ H₄ O₄ : Theory: C, 64.23; H, 5.61; N, 8.99. Found: C, 64.50; H,5.58; N, 8.78.

EXAMPLE 1835-((4-fluorobenzoyl)-N-methyl)amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolefumarate

To a solution of 0.59 gm (2.45 mMol)5-methylamino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 20 mLdimethylformamide were added 0.409 mL (2.9 mMol) triethylamine followedby 0.318 mL (2.7 mMol) 4-fluorobenzoyl chloride. After 3 hours thereaction mixture was diluted with 100 mL 2N sodium hydroxide followed by100 mL ethyl acetate. The phases were separated and the aqueousextracted with ethyl acetate. The organic extracts were combined andwashed sequentially with water and saturated aqueous sodium chloride.The remaining organics were dried over sodium sulfate and concentratedunder reduced pressure. The residue was subjected to flashchromatography, eluting with a gradient of dichloromethane containing0-5% methanol and 0-0.5% ammonium hydroxide. Fractions shown to containproduct were combined and concentrated under reduced pressure. Fumaratesalt was formed in and crystallized from ethyl acetate/ethanol to give0.868 gm (73.9%) of the title compound as a tan powder.

m.p.=203-206° C. (dec.); MS(m/e): 363(M⁺) Calculated for C₂₂ H₂₂ N₃OF.C₄ H₄ O₄ : Theory: C, 65.13; H, 5.47; N, 8.76. Found: C, 65.43; H,5.73; N, 8.92.

EXAMPLE 184 5-(2-tetrahydrofuranoyl)-3-(1-ethylpiperidin-4-yl)-1H-indoleoxalate

To a solution of 0.52 gm (1.55 mMol)5-(2-furoyl)amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indolein 50 mL ethanol and 25 mL tetrahydrofuran were added 0.13 gm 5%palladium on carbon and the mixture hydrogenated at ambient temperatureat an initial hydrogen pressure of 60 p.s.i. After 24 hours the reactionmixture was filtered and concentrated under reduced pressure. Theresidue was purified by radial chromatography (2 mm Silica), elutingwith 100:5:1 dichloromethane:methanol:ammonium hydroxide. Fractionsshown to contain product were combined and concentrated under reducedpressure. The residue was dissolved in ethyl acetate and treated with anequivalent of oxalic acid. The solid which formed was filtered, washedwith ethyl acetate and dried under reduced pressure to give 0.32 gm(47.9%) of the title compound as a white powder.

m.p.=103-105° C.; MS(m/e): 341(M⁺ 1) Calculated for: C₂₀ H₂₇ N₃ O₂ --C₂H₂ O₄ : Theory: C, 61.24; H, 6.77; N, 9.74. Found: C, 61.42; H, 6.80; N,9.65.

EXAMPLE 185 5-methanesulfonylamino-3-(1,2,3,6-pyridin-4-yl)-1H-indolehydrochloride

To a solution of 1.47 gm (26.2 mMol) potassium hydroxide in 10 mLmethanol were added 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indolein 5 mL methanol followed by 1.1 gm (7.1 mMol) 4-piperidonehydrochloride monohydrate. The resulting suspension was stirred atreflux for 18 hours. The reaction mixture was then concentrated underreduced pressure. The residual oil was then dissolved in water and thepH of the solution adjusted to 8.0 with 5.0 N hydrochloric acid. Thesolution was saturated with sodium chloride and then extracted withdichloromethane. The organic phases were combined and concentrated underreduced pressure. The residual solid was crystallized frommethanol/water to give 0.815 gm (52.2%) of the title compound as yellowneedles.

m.p.>250° C.; MS(m/e): 291(M⁺) Calculated for: C₁₄ H₁₇ N₃ SO₂ --HCl:Theory: C, 51.29; H, 5.53; N, 12.82. Found: C, 51.53; H, 5.55; N, 12.73.

EXAMPLE 1865-(4-fluorobenzoyl)amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

To a solution of 5.8 gm (90 mMol) potassium hydroxide in 75 mL methanolwere added 9.22 gm (60 mMol) 4-piperidone hydrochloride monohydratefollowed by 7.8 gm (30 mMol)5-(4-fluorobenzoyl)amino-3-(piperidin-4-yl)-1H-indole (Example 182A).This solution was stirred at reflux for 18 hours. The reaction mixturewas cooled to ambient and then poured slowly into 150 mL water,maintaining the temperature of the solution at about 20° C. Theresulting precipitate was filtered and recrystallized from ethanol togive 4.72 gm (47.2%) of the title compound as tan crystals. 0.725 gm ofthe material were crystallized again from ethanol to provide 0.241 gmlight yellow crystals for analysis.

m.p.=241° C. (dec.); MS(m/e): 335(M⁺) Calculated for: C₂₀ H₁₈ N₃ OF:Theory: C, 71.63; H, 5.41; N, 12.53. Found: C, 71.85; H, 5.50; N, 12.61.

EXAMPLE 187 5-(4-fluorobenzoyl)amino-3-(piperidin-4-yl)-1H-indole

Following the procedure described in detail in Example 30, 3.93 gm (11.7mMol)5-(4-fluorobenzoyl)amino-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolewere hydrogenated to give 1.83 gm (49%) of the title compound ascolorless crystals.

m.p.=229-230° C. (methanol); MS(m/e): 337(M⁺) Calculated for: C₂₀ H₂₀ N₃OF: Theory: C, 71.20; H, 5.98; N, 12.45. Found: C, 71.46; H, 6.17; N,12.40.

General Procedure for the Coupling of Amines with Indole 5-CarboxylicAcids

A mixture of 15 mg (0.058 mMol)5-carboxy-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole, 18 mg(0.088 mMol) dicyclohexylcabodiimide, 12 mg (0.088 mMol)hydroxybenztriazole, and 1.5 equivalents of an appropriate amine in 2 mLdimethylformamide are heated at 75° C. for 18 hours. The reaction isallowed to cool and is then loaded onto a VARIAN BOND ELUT SCX™ (Varian,Harbor City, Calif., U.S.A.) ion exchange column (3 mL/0.5 gm). Thecolumn is washed with 6 mL methanol and then the desired compound isstripped from the column by eluting with 2M ammonium hydroxide inmethanol. This eluant is concentrated under reduced pressure and theresidue dissolved in 2 mL dichloromethane. To this solution is added0.118 gm (0.118 mMol) of a polystyrene bound isocyanate resin and themixture agitated for 18 hours. The reaction mixture is filtered andconcentrated under reduced pressure to provide the amides of theinvention If desired, the compound may be further purified by loadingonto a VARIAN BOND ELUT SAX™ (Varian, Harbor City, Calif., U.S.A.) ionexchange column (10 mL/0.5 gm). The desired compound is stripped fromthe column by eluting with methanol and concentrating the eluant underreduced pressure. The compounds of Examples 188-202 were prepared bythis procedure.

EXAMPLE 188 N-(pyridin-2-yl)methyl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 2-aminomethylpyridine, 5.2 mg (26%) of the title compound wasrecovered.

MS(m/e): 337(M+1)

EXAMPLE 189 N-(pyridin-3-yl)methyl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 3-aminomethylpyridine, 8.3 mg (42%) of the title compound wasrecovered.

MS(m/e): 337(m+1)

EXAMPLE 190 N-(pyridin-4-yl)methyl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 4-aminomethylpyridine, 7.9 mg (40%) of the title compound wasrecovered.

MS(m/e): 337(M+1)

EXAMPLE 191 N-(fur-2-yl)methyl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 2-aminomethylfuran, 8.0 mg (51%) of the title compound wasrecovered.

MS(m/e): 335(M⁺)

EXAMPLE 192 N-(tetrahydrofur-2-yl)methyl!-5-carboxamido-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 2-aminomethyltetrahydrofuran, 3.8 mg (20%) of the title compoundwas recovered.

MS(m/e): 340(M+1)

EXAMPLE 1935-(pyrrolidin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using pyrrolidine, 7.1 mg (39%) of the title compound was recovered.

MS(m/e): 309(M⁺)

EXAMPLE 1945-(piperidin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using piperidine, 9.7 mg (51%) of the title compound was recovered.

MS(m/e): 323(M⁺)

EXAMPLE 1955-(morpholin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using morpholine, 7.2 mg (38%) of the title compound was recovered.

MS(m/e): 325(M⁺)

EXAMPLE 1965-(thiomorpholin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using thiomorpholine, 11.2 mg (56%) of the title compound was recovered.

MS(m/e): 341(M⁺)

EXAMPLE 1975-(4-hydroxypiperidin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 4-hydroxypiperidine, 3.6 mg (18%) of the title compound wasrecovered.

MS(m/e): 340(M+1)

EXAMPLE 1985-(3-hydroxymethylpiperidin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 3-hydroxymethylpiperidine, 10.1 mg (49%) of the title compound wasrecovered.

MS(m/e): 353(M⁺)

EXAMPLE 1995-(3-(N,N-diethylcarboxamido)piperidin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 3-(N,N-diethylcarboxamido)piperidine, 11.0 mg (44%) of the titlecompound was recovered.

MS(m/e): 422(M⁺)

EXAMPLE 2005-(4-cyclopentylpiperazin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 4-cyclopentylpiperazine, 8.7 mg (38%) of the title compound wasrecovered.

MS(m/e): 393(M+1)

EXAMPLE 2015-(4-(2-methoxyethyl)piperazin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 4-(2-methoxyethyl)piperazine, 9.6 mg (43%) of the title compoundwas recovered

MS (m/e)| 383 (M+1)

EXAMPLE 2025-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole

Using 4-(pyridin-2-yl)piperazine, 8.6 mg (36%) of the title compound wasrecovered

MS(m/e): 402(M+1)

To demonstrate the use of the compounds of this invention in thetreatment of migraine, their ability to bind to the 5-HT_(1F) receptorsubtype was determined. The ability of the compounds of this inventionto bind to the 5-HT_(1F) receptor subtype was measured essentially asdescribed in N. Adham, et al., Proceedings of the National Academy ofSciences (USA), 90, 408-412 (1993).

Membrane Preparation: Membranes were prepared from transfected Ltk-cells which were grown to 100% confluency. The cells were washed twicewith phosphate-buffered saline, scraped from the culture dishes into 5mL of ice-cold phosphate-buffered saline, and centrifuged at 200×g for 5minutes at 4° C. The pellet was resuspended in 2.5 mL of ice-cold Trisbuffer (20 mM Tris HCl, pH=7.4 at 23° C., 5 mM EDTA) and homogenizedwith a Wheaton tissue grinder. The lysate was subsequently centrifugedat 200×g for 5 minutes at 4° C. to pellet large fragments which werediscarded. The supernatant was collected and centrifuged at 40,000×g for20 minutes at 4° C. The pellet resulting from this centrifugation waswashed once in ice-cold Tris wash buffer and resuspended in a finalbuffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH=7.4 at 23° C.Membrane preparations were kept on ice and utilized within two hours forthe radioligand binding assays. Protein concentrations were determinedby the method of Bradford (Anal. Biochem., 72, 248-254 (1976)).

Radioligand Binding: ³ H-5-HT! binding was performed using slightmodifications of the 5HT_(1D) assay conditions reported by Herrick-Davisand Titeler (J. Neurochem., 50, 1624-1631 (1988)) with the omission ofmasking ligands. Radioligand binding studies were achieved at 37° C. ina total volume of 250 μL of buffer (50 mM Tris, 10 mM MgCl₂, 0.2 mMEDTA, 10 μM pargyline, 0.1% ascorbate, pH=7.4 at 37° C.) in 96 wellmicrotiter plates. Saturation studies were conducted using ³ H!5-HT at12 different concentrations ranging from 0.5 nM to 100 nM. Displacementstudies were performed using 4.5-5.5 nM ³ H!5-HT. The binding profile ofdrugs in competition experiments was accomplished using 6-12concentrations of compound. Incubation times were 30 minutes for bothsaturation and displacement studies based upon initial investigationswhich determined equilibrium binding conditions. Nonspecific binding wasdefined in the presence of 10 μM 5-HT. Binding was initiated by theaddition of 50 μL membrane homogenates (10-20 μg). The reaction wasterminated by rapid filtration through presoaked (0.5%poylethyleneimine) filters using 48R Cell Brandel Harvester(Gaithersburg, Md.). Subsequently, filters were washed for 5 secondswith ice cold buffer (50 mM Tris HCl, pH=7.4 at 4° C.), dried and placedinto vials containing 2.5 mL Readi-Safe (Beckman, Fullerton, Calif.) andradioactivity was measured using a Beckman LS 5000TA liquidscintillation counter. The efficiency of counting of ³ H!5-HT averagedbetween 45-50%. Binding data was analyzed by computer-assisted nonlinearregression analysis (Accufit and Accucomp, Lunden Software, ChagrinFalls, Ohio). IC₅₀ values were converted to K_(i) values using theCheng-Prusoff equation (Biochem. Pharmacol., 22, 3099-3108 (1973). Allexperiments were performed in triplicate. Representative compounds ofthis invention were found to have affinity for the 5-HT_(1F) receptor asmeasured by the procedure described supra.

As was reported by R. L. Weinshank, et al., WO93/14201, the 5-HT_(1F)receptor is functionally coupled to a G-protein as measured by theability of serotonin and serotonergic drugs to inhibit forskolinstimulated cAMP production in NIH3T3 cells transfected with the5-HT_(1F) receptor. Adenylate cyclase activity was determined usingstandard techniques. A maximal effect is achieved by serotonin. AnE_(max) is determined by dividing the inhibition of a test compound bythe maximal effect and determining a percent inhibition. (N. Adham, etal., supra,; R. L. Weinshank, et al., Proceedings of the NationalAcademy of Sciences (USA), 89,3630-3634 (1992)), and the referencescited therein

Measurement of cAMP Formation

Transfected NIH3T3 cells (estimated Bmax from one point competitionstudies=488 fmol/mg of protein) were incubated in DMEM, 5 mMtheophylline, 10 mM HEPES (4- 2-hydroxyethyl!-1-piperazineethanesulfonicacid) and 10 μM pargyline for 20 minutes at 37° C., 5% CO₂. Drugdose-effect curves were then conducted by adding 6 different finalconcentrations of drug, followed immediately by the addition offorskolin (10 μM). Subsequently, the cells were incubated for anadditional 10 minutes at 37° C., 5% CO₂. The medium was aspirated andthe reaction was stopped by the addition of 100 MM HCl. To demonstratecompetitive antagonism, a dose-response curve for 5-HT was measured inparallel, using a fixed dose of methiothepin. (0.32 μM) The plates werestored at 4° C. for 15 minutes and then centrifuged for 5 minutes at500×g to pellet cellular debris, and the supernatant was aliquoted andstored at -20° C. before assessment of cAMP formation byradioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics,Cambridge, Mass.). Radioactivity was quantified using a Packard COBRAAuto Gamma counter, equipped with data reduction software. All of thecompounds shown to have affinity for the 5-HT_(1F) receptor were testedand found to be agonists at the 5-HT_(1F) receptor in the cAMP assay.

The discovery that the pain associated with migraine and associateddisorders is inhibited by activation of the 5-HT_(1F) receptor byadministration of 5-HT_(1F) agonists required the analysis of data fromdiverse assays of pharmacological activity. To establish that the5-HT_(1F) receptor subtype is responsible for mediating neurogenicmeningeal extravasation which leads to the pain of migraine, the bindingaffinity of a panel of compounds to serotonin receptors was measuredfirst, using standard procedures. For example, the ability of a compoundto bind to the 5-HT_(1F) receptor subtype was performed as describedsupra. For comparison purposes, the binding affinities of compounds tothe 5-HT_(1D)α, 5-HT_(1D)β, and 5-HT_(1E) receptors were also determinedas described supra, except that different cloned receptors were employedin place of the 5-HT_(1F) receptor clone employed therein. The samepanel was then tested in the cAMP assay to determine their agonist orantagonist character. Finally, the ability of these compounds to inhibitneuronal protein extravasation, a functional assay for migraine pain,was measured.

The panel of compounds used in this study represents distinct structuralclasses of compounds which were shown to exhibit a wide range ofaffinities for the serotonin receptors assayed. Additionally, the panelcompounds were shown to have a wide efficacy range in the neuronalprotein extravasation assay as well. The panel of compounds selected forthis study are described below.

COMPOUND I 3-2-(dimethylamino)ethyl!-N-methyl-1H-indole-5-methanesulfonamidebutane-1,4-dioate (1:1) (Sumatriptan succinate) ##STR8##

Sumatriptan succinate is commercially available as Imitrex™ or may beprepared as described in U.S. Pat. No. 5,037,845, issued Aug. 6, 1991,which is herein incorporated by reference.

COMPOUND II5-fluoro-3-<1-<2-<1-methyl-1H-pyrazol-4-yl>ethyl>-4-piperidinyl>-1H-indolehydrochloride ##STR9##

Compound II is available by the following procedure.

2-(1-methyl-3-pyrazolo)-1-ethanol

To a mixture of 200 gm (2.85 mole) 2,3-dihydrofuran and 800 mL (4.81mole) triethylorthoformate were added 0.8 mL (6.5 mMol) borontrifluoride diethyl etherate dropwise. After an initial exotherm thereaction mixture was allowed to stir at ambient temperature for fourdays. To the reaction mixture was then added 4.0 gm potassium carbonateand the reaction mixture was distilled under 6.0 mm Hg. Fractionsdistilling between 60° C. and 130° C. were collected to give 261.64 gm(42.1%) of a light yellow oil.

MS(m/e): 219(M⁺)

To a solution of 87.2 gm (0.40 mole) of the previously prepared yellowoil in 787 mL 1N HCl were added 21.3 mL (0.40 mole) methyl hydrazine andthe reaction mixture was stirred at reflux for four hours. The reactionmixture was cooled to ambient temperature and the volatiles were removedunder reduced pressure. The residual oil was treated with 2N NaOH untilbasic and the aqueous extracted well with dichloromethane. The combinedorganic extracts were dried over sodium sulfate and concentrated underreduced pressure to give 32.15 gm (64.5%) of the title compound as abrown oil.

MS(m/e): 126(M⁺) ¹ H-NMR(DMSO-d₆): δ7.45 (s, 1H); 7.25 (s, 1H); 4.65 (t,1H); 3.75 (s,3H); 3.55 (m, 2H); 2.55 (t, 2H).

1-methyl-4-(2-methanesulfonyloxyethyl)pyrazole

To a solution of 16.0 gm (127 mMol) 2-(1-methyl-3-pyrazolo)-1-ethanoland 27 mL (193 mMol) triethylamine in 550 mL tetrahydrofuran were added10.8 mL (40 mMol) methanesulfonyl chloride with icebath cooling. Oncethe addition was complete, the reaction mixture was stirred at ambientfor 4 hours. The volatiles were then removed under reduced pressure andthe residue partitioned between water and dichloromethane. The organicphase was washed with water followed by saturated aqueous sodiumchloride and the remaining organics dried over sodium sulfate. Thesolvent was removed under reduced pressure to give a crude yield of 28.4gm of the title compound as a brown oil. The product was used withoutfurther purification.

5-fluoro-3- 1,2,3,6-tetrahydro-4-pyridyl!-1H-indole

To a solution of 74 gm potassium hydroxide in 673 mL methanol were added10.0 gm (74 mMol) 5-fluoroindole and 23.3 gm (151 mMol)4-piperidone.HCl.H₂ O. The reaction mixture was stirred at reflux for 18hours. The reaction mixture was diluted with 1.3 L of water and theresulting precipitate recovered by filtration and dried under reducedpressure to give 10.75 gm (67.2%) of 5-fluoro-3-1,2,5,6-tetrahydro-4-pyridyl!-1H-indole as a yellow solid.

5-fluoro-3-(4-piperidinyl)-1H-indole

To a solution of 10.75 gm (50 mMol) 5-fluoro-3-1,2,5,6-tetrahydro-4-pyridyl!-1H-indole in 500 mL ethanol were added 2.0gm 5% palladium on carbon and the reaction mixture hydrogenated atambient temperature for 18 hours at an initial hydrogen pressure of 60p.s.i. The reaction mixture was then filtered through a pad of celiteand the filtrate concentrated under reduced pressure to give anoff-white solid. The solid was recrystallized from methanol to give 8.31gm (76.2%) of the title compound as a colorless solid.

m.p.=229-230° C.; MS(m/e): 218(M⁺) Calculated for C₁₃ H₁₅ N₂ F: Theory:C, 71.53; H, 6.93; N, 12.83. Found: C, 71.81; H, 7.02; N, 12.80.

Alkylation

To a solution of 2.0 gm (9.2 mMol) 5-fluoro-3-(4-piperidinyl)-1H-indoleand 2.4 gm (23 mMol) sodium carbonate in 50 mL dimethylformamide wereadded 1.87 gm (9.2 mMol) 1-methyl-4-(2-methanesulfonyloxyethyl)pyrazolein 5 mL dimethylformamide. The reaction mixture was stirred at 100° C.for 18 hours. The reaction mixture was cooled to ambient and the solventremoved under reduced pressure. The residue was partitioned betweendichloromethane and water and the phases separated. The organic phasewas washed well with water followed by saturated aqueous sodiumchloride. The remaining organic phase was dried over sodium sulfate andconcentrated under reduced pressure. The residual oil was subjected tosilica gel chromatography, eluting with 20:1 dichloromethane:methanol.Fractions shown to contain the desired compound were combined andconcentrated under reduced pressure to give a yellow oil. The oil wasconverted to the hydrochloride salt and was crystallized from ethylacetate/methanol. 1.61 gm (51.1%) of Compound II were recovered ascolorless crystals.

m.p.=239° C.; MS(m/e): 326(M⁺) Calculated for C₁₉ H₂₃ N₄ F.HCl: Theory:C, 62.89; H, 6.67; N, 15.44. Found: C, 62.80; H, 6.85; N, 15.40.

COMPOUND III 5-hydroxy-3-(4-piperidinyl)-1H-indole oxalate ##STR10##

Compound III is available by the following procedure.

5-benzyloxy-3- 1,2,5,6-tetrahydro-4-pyridinyl!-1H-indole

Starting with 5.0 gm (22 mMol) 5-benzyloxyindole and 6.88 gm (45 mMol)4-piperidone.HCl.H₂ O, 6.53 gm (97.6%) of 5-benzyloxy-3-1,2,5,6-tetrahydro-4-pyridinyl!-1H-indole were recovered as a lightyellow solid by the procedure described in Preparation I. The materialwas used in the subsequent step without further purification.

Hydrogenation/Hydrogenolysis

To a solution of 1.23 gm (4 mMol) 5-benzyloxy-3-1,2,5,6-tetrahydro-4-pyridinyl!-1H-indole in 50 mL 1:1tetrahydrofuran:ethanol were added 0.3 gm 5% palladium on carbon and thereaction mixture hydrogenated at ambient temperature for 18 hours withan initial hydrogen pressure of 60 p.s.i. The reaction mixture was thenfiltered through a celite pad and the filtrate concentrated underreduced pressure. The residue was converted to the oxalate salt and 0.98gm (80.0%) of Compound III were recovered as a brown foam.

m.p.=67° C.; MS(m/e): 216(M⁺) Calculated for C₁₃ H₁₆ N₂ O.C₂ H₂ O₄ :Theory: C, 58.81; H, 5.92; N, 9.14. Found: C, 58.70; H, 5.95; N, 9.39.

COMPOUND IV 8-chloro-2-diethylamino-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR11##

Compound IV is available by the following procedure.

8-chloro-2-tetralone

A mixture of 30.0 gm (0.176 mole) of o-chlorophenylacetic acid and 40.0mL of thionyl chloride was stirred at ambient temperature for 18 hours.The volatiles were then removed in vacuo to give 32.76 gm (99.0%) ofo-chlorophenylacetyl chloride as a transparent, pale yellow, mobileliquid.

NMR(CDCl₃): 7.5-7.1 (m, 4H), 4.2 (s, 2H).

To a slurry of 46.5 gm (0.348 mole) AlCl₃ in 400 mL dichloromethane at-78° C. was added a solution of 32.76 gm (0.174 mole) of the previouslyprepared o-chlorophenylacetyl chloride in 100 mL dichloromethanedropwise over 1 hour. The dry ice/acetone bath then was replaced with anice/water bath and ethylene was bubbled into the reaction mixture duringwhich time the temperature rose to 15° C. The ethylene addition wasdiscontinued at the end of the exotherm and the reaction mixture wasstirred at about 5° C. for 4 hours. Ice was then added to the reactionmixture to destroy aluminum complexes. Upon termination of the exotherm,the reaction mixture was diluted with 500 mL of water and stirredvigorously until all solids had dissolved. The phases were separated andthe organic phase was washed with 3×400 mL 1N hydrochloric acid and2×400 mL saturated aqueous sodium bicarbonate. The remaining organicphase was then dried over sodium sulfate and concentrated in vacuo togive a pale orange residue. The residue was dissolved in 1:1hexane:diethyl ether and was poured over a flash silica column which wasthen eluted with 1:1 hexane:diethyl ether to give a light yellow residuewhich was crystallized from 4:1 hexane:diethyl ether to give 10.55 gm ofthe title compound.

NMR(CDCl₃): 7.5-7.2 (m, 3H), 3.7 (s, 2H), 3.3-3.0 (t, J=7 Hz, 2H),2.8-2.4 (t, J=7 Hz, 2H). MS: 180(60), 165(9), 138(100), 117(52),115(50), 103(48), 89(20), 76(25), 74(18), 63(30), 57(9), 52(28), 51(20),42(6), 39(32). IR(nujol mull): 2950 cm⁻¹, 2927 cm⁻¹, 1708 cm⁻¹, 1464cm⁻¹, 1450 cm⁻¹, 1169 cm⁻¹, 1141 cm⁻¹.

Reductive Amination

To a solution of 0.5 gm (2.78 mMol) 8-chloro-2-tetralone in 25 mLcyclohexane were added 1.4 mL (13.9 mMol) diethylamine followed by 0.1gm p-toluenesulfonic acid monohydrate. The reaction mixture was thenheated at reflux with constant water removal (Dean-Stark Trap) for 18hours. The reaction mixture was then cooled to ambient and the volatilesremoved under reduced pressure. The residue was then dissolved in 15 mLmethanol to which were then added 1.5 mL acetic acid followed by theportionwise addition of 0.5 gm sodium borohydride. The reaction mixturewas then stirred for 1 hour at ambient.

The reaction mixture was then diluted with 20 mL 10% HCl and stirred foran additional hour. The mixture was then extracted with diethyl etherand the remaining aqueous phase was poured over ice, made basic withammonium hydroxide and extracted well with dichloromethane. Theseextracts were combined, dried over sodium sulfate and concentrated underreduced pressure. The residue was redissolved in dichloromethane andsubjected to chromatography over basic alumina, eluting withdichloromethane. Fractions shown to contain product were combined andconcentrated under reduced pressure. The residual oil was dissolved indiethyl ether and the solution saturated with hydrogen chloride. Theviscous residue was crystallized from acetone/diethyl ether to give 0.20gm (23.2%) of Compound IV as colorless crystals.

m.p.=158-159° C.; MS(m/e): 273 Calculated for C₁₄ H₂₁ NCl.HCl: Theory:C, 61.32; H, 7.72; N, 5.11. Found: C, 61.62; H, 7.94; N, 5.03.

COMPOUND V 6-hydroxy-3-dimethylamino-1,2,3,4-tetrahydrocarbazole##STR12##

Compound V is available by the following procedure.

4-dimethylamino-1-cyclohexanone ethylene ketal

To a solution of 5.0 gm (32 mMol) 1,4-cyclohexanedione mono-ethyleneketal and 10.80 gm (240 mMol) dimethylamine were added 2.0 mL aceticacid and the mixture was stirred at 0° C. for 1.5 hours. To thissolution were then added 3.62 gm (58 mMol) sodium cyanoborohydride andthe reaction stirred for an additional hour at ambient. The pH of thereaction mixture was adjusted to ˜7 with 16 mL acetic acid and stirred18 hours at ambient. The volatiles were removed under reduced pressureand the residue dissolved in cold 5% tartaric acid solution and then theaqueous phase was made basic with 5N sodium hydroxide. This aqueousphase was extracted well with dichloromethane. These organic extractswere combined and concentrated under reduced pressure to give 5.04 gm(85%) of the title compound as an oil.

4-dimethylamino-1-cyclohexanone

4.96 gm (26.8 mMol) 4-dimethylamino-1-cyclohexanone ethylene ketal weredissolved in 50 mL formic acid and the solution stirred at reflux for 18hours. The reaction mixture was then cooled to ambient and the volatilesremoved under reduced pressure to give 3.78 gm (100%) of the titlecompound.

6-benzyloxy-3-dimethylamino-1,2,3,4-tetrahydrocarbazole

To a solution of 3.78 gm (26.8 mMol) 4-dimethylamino-1-cyclohexanone and6.69 gm (26.8 mMol) 4-benzyloxyphenylhydrazine hydrochloride in 50 mLethanol were added 2.17 mL (26.8 mMol) pyridine. To this solution wereadded 5×10 mL portions of water and the reaction mixture then stored at0° C. for 18 hours. The reaction mixture was then diluted with anadditional 50 mL of water and the mixture extracted well withdichloromethane. The combined organic extracts were dried over sodiumsulfate and the volatiles removed under reduced pressure. The residualoil was subjected to flash silica gel chromatography, eluting with 9:1chloroform:methanol. Fractions shown to contain the desired product werecombined and concentrated under reduced pressure to give 2.14 gm (24.9%)of the title compound.

Hydrogenolysis

To a solution of 2.14 gm (6.7 mMol)6-benzyloxy-3-dimethylamino-1,2,3,4-tetrahydrocarbazole in 50 mL ethanolwere added 0.20 gm 10% palladium on carbon and the reaction mixture washydrogenated at ambient temperature with an initial hydrogen pressure of40 p.s.i. After 5 hours an additional charge of 0.20 gm 10% palladium oncarbon were added and the reaction mixture repressurized with hydrogento 40 p.s.i. for 4 hours. The reaction mixture was then filtered througha pad of celite and the filtrate concentrated under reduced pressure.The residue was subjected to Florisil chromatography, eluting with 9:1chloroform:methanol. Fractions shown to contain the desired compoundwere combined and concentrated under reduced pressure. The residue wasagain subjected to Florisil chromatography, eluting with a gradientconsisting of chloroform containing 2-10% methanol. Fractions shown tocontain product were combined and concentrated under reduced pressure togive Compound V as a crystalline solid.

MS(m/e): 230(M⁺); Calculated for C₁₄ H₁₈ N₂ O: Theory: C, 73.01; H,7.88; N, 12.16. Found: C, 72.75; H, 7.83; N, 11.97.

Binding Assays

The binding affinities of compounds for various serotonin receptors weredetermined essentially as described above except that different clonedreceptors are employed in place of the 5-HT_(1F) receptor clone employedtherein. The results of these binding experiments are summarized inTable I.

                  TABLE I    ______________________________________    BINDING TO SEROTONIN (5-HT.sub.1) RECEPTOR SUBTYPES (K.sub.i nM)    Compound   5-HT.sub.1Dα                        5-HT.sub.1Dβ                                   5-HT.sub.1E                                         5-HT.sub.1F    ______________________________________    I          4.8      9.6        2520.0                                         25.7    II         21.7     53.6       50.3  2.5    III        163.2    196.5      3.9   22.0    IV         13.5     145.3      813.0 129.2    V          791.0    1683.0     73.6  10.3    ______________________________________

cAMP Formation

All of the compounds of the panel were tested in the cAMP formationassay described supra and all were found to be agonists of the 5-HT_(1F)receptor.

Protein Extravasation

Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles RiverLaboratories (225-325 g) were anesthetized with sodium pentobarbitalintraperitoneally (65 mg/kg or 45 mg/kg respectively) and placed in astereotaxic frame (David Kopf Instruments) with the incisor bar set at-3.5 mm for rats or -4.0 mm for guinea pigs. Following a midline sagitalscalp incision, two pairs of bilateral holes were drilled through theskull (6 mm posteriorly, 2.0 and 4.0 mm laterally in rats; 4 mmposteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinatesreferenced to bregma). Pairs of stainless steel stimulating electrodes(Rhodes Medical Systems, Inc.) were lowered through the holes in bothhemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) fromdura.

The femoral vein was exposed and a dose of the test compound wasinjected intravenously (1 mL/kg). Approximately 7 minutes later, a 50mg/kg dose of Evans Blue, a fluorescent dye, was also injectedintravenously. The Evans Blue complexed with proteins in the blood andfunctioned as a marker for protein extravasation. Exactly 10 minutespost-injection of the test compound, the left trigeminal ganglion wasstimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msecduration) with a Model 273 potentiostat/galvanostat (EG&G PrincetonApplied Research).

Fifteen minutes following stimulation, the animals were killed andexsanguinated with 20 mL of saline. The top of the skull was removed tofacilitate the collection of the dural membranes. The membrane sampleswere removed from both hemispheres, rinsed with water, and spread flaton microscopic slides. Once dried, the tissues were coverslipped with a70% glycerol/water solution.

A fluorescence microscope (Zeiss) equipped with a grating monochromatorand a spectrophotometer was used to quantify the amount of Evans Bluedye in each sample. An excitation wavelength of approximately 535 nm wasutilized and the emission intensity at 600 nm was determined. Themicroscope was equipped with a motorized stage and also interfaced witha personal computer. This facilitated the computer-controlled movementof the stage with fluorescence measurements at 25 points (500 μm steps)on each dural sample. The mean and standard deviation of themeasurements was determined by the computer.

The extravasation induced by the electrical stimulation of thetrigeminal ganglion was an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the other (unstimulated) half of the dura to be used as acontrol. The ratio of the amount of extravasation in the dura from thestimulated side compared to he unstimulated side dura was calculated.Saline controls yielded a ratio of approximately 2.0 in rats and 1.8 inguinea pigs. In contrast, a compound which effectively prevented theextravasation in the dura from the stimulated side would have a ratio ofapproximately 1.0. A dose-response curve was generated and the dose thatinhibited the extravasation by 50% (ID₅₀) was approximated. This data ispresented in Table II.

                  TABLE II    ______________________________________    Inhibition of Protein Extravasation (ID.sub.50 mMol/kg)                  i.v. ID.sub.50    Compound      (mMol/kg)    ______________________________________    I             2.6 × 10.sup.-8    II             8.6 × 10.sup.-10    III           8.9 × 10.sup.-9    IV            1.2 × 10.sup.-7    V             8.7 × 10.sup.-9    ______________________________________

To determine the relationship of binding at various serotonin receptorsto inhibition of neuronal protein extravasation, the binding affinity ofall of the compounds to each of the 5-HT_(1D)α, 5-HT_(1D)β, 5-HT_(1E)and 5-HT_(1F) receptors was plotted against their ID₅₀ in the proteinextravasation model. A linear regression analysis was performed on eachset of data and a correlation factor, R², calculated. The results ofthis analysis are summarized in Table III.

                  TABLE III    ______________________________________    Correlation Factor (R.sup.2) for Specific 5-HT.sub.1 Subtype Binding    Affinity vs Inhibition of Protein Extravasation    5-HT.sub.1 Subtype                  Correlation Factor (R.sup.2)    ______________________________________    5-HT.sub.1Dα                  0.07    5-HT.sub.1Dβ                  0.001    5-HT.sub.1E   0.31    5-HT.sub.1F   0.94    ______________________________________

An ideally linear relationship would generate a correlation factor of1.0, indicating a cause and effect relationship between the twovariables. The experimentally determined correlation factor betweeninhibition of neuronal protein extravasation and 5-HT_(1F) bindingaffinity is 0.94. This nearly ideal dependence of the ID₅₀ in theprotein extravasation model on binding affinity to the 5-HT_(1F)receptor clearly demonstrates that the 5-HT_(1F) receptor mediates theinhibition of protein extravasation resulting from stimulation of thetrigeminal ganglia.

Sumatriptan exhibits low bioavailability and relatively short durationof action. Its affinity for a number of serotonin receptor subtypesgives rise to undesirable side effects, particularly vasoconstriction,which severely limits its utility in the treatment of migraine. Thecompounds of this invention, however, are highly bioavailable throughseveral routes of administration including, but not limited to, oral,buccal, intravenous, subcutaneous, intranasal, intraocular, transdermal,rectal and by inhalation. They exhibit a rapid onset and long durationof action, typically requiring only a single dose per day to maintaintherapeutic levels. Since compounds of this invention are potentagonists of the 5-HT_(1F) receptor, extremely low doses are required tomaintain therapeutic levels. Additionally, due to the high selectivityof compounds of this invention for the 5-HT_(1F) receptor, complicationsdue to vasoconstriction are avoided. Compounds of this invention alsoinhibit protein extravasation if administered prior or subsequent tostimulation of the trigeminal ganglia, suggesting they may beadministered prior to an incipient migraine attack to prevent pain, orduring a migraine attack to alleviate pain.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These compositions can be administered by a varietyof routes including oral, buccal, rectal, intranasal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Many of thecompounds employed in the methods of this invention are effective asboth injectable and oral compositions. Such compositions are prepared ina manner well known in the pharmaceutical art and comprise at least oneactive compound. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16thed. 1980).

In making the compositions employed in the present invention the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within such a carrier which can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium) ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about, 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.001 to about 100 mg, more usually about1.0 to about 30 mg, of the active ingredient. The term "unit dosageform" refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compounds are generally effective over a wide dosage range.For examples, dosages per day normally fall within the range of about0.0001 to about 30 mg/kg of body weight. In the treatment of adulthumans, the range of about 0.1 to about 15 mg/kg/day, in single ordivided dose, is especially preferred. However, it will be understoodthat the amount of the compound actually administered will be determinedby a physician, in the light of the relevant circumstances, includingthe condition to be treated, the chosen route of administration, theactual compound or compounds administered, the age, weight, and responseof the individual patient, and the severity of the patient's symptoms,and therefore the above dosage ranges are not intended to limit thescope of the invention in any way. In some instances dosage levels belowthe lower limit of the aforesaid range may be more than adequate, whilein other cases still larger doses may be employed without causing anyharmful side effect, provided that such larger doses are first dividedinto several smaller doses for administration throughout the day.

FORMULATION EXAMPLE

    ______________________________________    Hard gelatin capsules containing the following    ingredients are prepared:                      Quantity    Ingredient        (mg/capsule)    ______________________________________    Compound of Example 30                      30.0    Starch            305.0    Magnesium stearate                      5.0    ______________________________________

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below:

    ______________________________________                      Quantity    Ingredient        (mg/tablet)    ______________________________________    Compound of Example 129                      25.0    Cellulose, microcrystalline                      200.0    Colloidal silicon dioxide                      10.0    Stearic acid      5.0    ______________________________________

The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

    ______________________________________    Ingredient         Weight %    ______________________________________    Compound of Example 142                       5    Lactose            95    ______________________________________

The active mixture is mixed with the lactose and the mixture is added toa dry powder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

    ______________________________________                           Quantity    Ingredient             (mg/tablet)    ______________________________________    Compound of Example 41 30.0   mg    Starch                 45.0   mg    Microcrystalline cellulose                           35.0   mg    Polyvinylpyrrolidone   4.0    mg    (as 10% solution in water)    Sodium carboxymethyl starch                           4.5    mg    Magnesium stearate     0.5    mg    Talc                   1.0    mg    Total                  120    mg    ______________________________________

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50-60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:

    ______________________________________                           Quantity    Ingredient             (mg/capsule)    ______________________________________    Compound of Example 51 40.0   mg    Starch                 109.0  mg    Magnesium stearate     1.0    mg    Total                  150.0  mg    ______________________________________

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

    ______________________________________    Ingredient              Amount    ______________________________________    Compound of Example 98  25     mg    Saturated fatty acid glycerides to                            2,000  mg    ______________________________________

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose aremade as follows:

    ______________________________________    Ingredient               Amount    ______________________________________    Compound of Example 99   50.0   mg    Xanthan gum              4.0    mg    Sodium carboxymethyl cellulose (11%)                             50.0   mg    Microcrystalline cellulose (89%)    Sucrose                  1.75   g    Sodium benzoate          10.0   mg    Flavor and Color         q.v.    Purified water to        5.0    ml    ______________________________________

The medicament, sucrose and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethyl cellulose inwater. The sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

FORMULATION EXAMPLE 8

Capsules, each containing 15 mg of medicament, are made as follows:

    ______________________________________                           Quantity    Ingredient             (mg/capsule)    ______________________________________    Compound of Example 105                           15.0   mg    Starch                 407.0  mg    Magnesium stearate     3.0    mg    Total                  425.0  mg    ______________________________________

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 425 mg quantities.

FORMULATION EXAMPLE 9

An intravenous formulation may be prepared as follows:

    ______________________________________    Ingredient             Quantity    ______________________________________    Compound of Example 106                           250.0  mg    Isotonic saline        1000   ml    ______________________________________

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows:

    ______________________________________    Ingredient             Quantity    ______________________________________    Compound of Example 118                           1-10    g    Emulsifying Wax        30      g    Liquid Paraffin        20      g    White Soft Paraffin    to 100  g    ______________________________________

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

FORMULATION EXAMPLE 11

Sublingual or buccal tablets, each containing 10 mg of activeingredient, may be prepared as follows:

    ______________________________________                           Quantity    Ingredient             Per Tablet    ______________________________________    Compound of Example 88 10.0   mg    Glycerol               210.5  mg    Water                  143.0  mg    Sodium Citrate         4.5    mg    Polyvinyl Alcohol      26.5   mg    Polyvinylpyrrolidone   15.5   mg    Total                  410.0  mg    ______________________________________

The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50-55° C. and themedicament is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2-4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices ("patches"). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which isherein incorporated by reference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

The type of formulation employed for the administration of the compoundsemployed in the methods of the present invention may be dictated by theparticular compounds employed, the type of pharmacokinetic profiledesired from the route of administration and the compound(s), and thestate of the patient.

we claim:
 1. A compound of Formula I: ##STR13## in which A--B is--CH--CH₂ -- or --C═CH--;R is H or C₁ -C₆ alkyl; R¹ is H or C₁ -C₄alkyl; X is --S--R², or --C(O)R³ ; whereR² is phenyl(C₁ -C₄ alkylene),or phenyl(C₁ -C₄ alkylene) substituted in the phenyl ring; R³ isnaphthyl, N-methyl-N-methoxyamino, heteroaryl, substituted heteroaryl,heteroaryl(C₁ -C₄ alkyl), or substituted heteroaryl(C₁ -C₄ alkyl); andpharmaceutically acceptable acid addition salts and solvates thereof. 2.A compound of claim 1, in which A--B is --C═CH--.
 3. A compound of claim1, in which A--B is --CH--CH₂ --.
 4. A compound of claim 1, in which R¹is H.
 5. A pharmaceutical formulation which comprises, in associationwith a pharmaceutically acceptable carrier, diluent or excipient, acompound of formula: ##STR14## in which A--B is --CH--CH₂ -- or--C═CH--;R is H or C₁ -C₆ alkyl; R¹ is H or C₁ -C₄ alkyl; X is --S--R²,or --C(O)R³ ;where R² is phenyl(C₁ -C₄ alkylene), or phenyl(C₁ -C₄alkylene) substituted in the phenyl ring; R³ is naphthyl,N-methyl-N-methoxyamino, heteroaryl, substituted heteroaryl,heteroaryl(C₁ -C₄ alkyl), or substituted heteroaryl(C₁ -C₄ alkyl); orpharmaceutically acceptable acid addition salts and solvates thereof. 6.A pharmaceutical formulation of claim 5, in which A--B is --C═CH--.
 7. Apharmaceutical formulation of claim 5, in which A--B is --CH--CH₂ --. 8.A pharmaceutical formulation of claim 5, in which R is H.
 9. A methodfor the activation of 5-HT_(1F) receptors in mammals, comprisingadministering to a mammal in need of such activation an effective amountof a compound of formula: ##STR15## in which A--B is --CH--CH₂ -- or--C═CH--:R is H or C₁ -C₆ alkyl; R¹ is H or C₁ -C₄ alkyl; X is --S--R²,or --C(O)R³ ; R² is phenyl, substituted phenyl, phenyl(C₁ -C₄ alkylene),phenyl(C₁ -C₄ alkylene) substituted in the phenyl ring, or pyridinyl; R³is C₁ -C₆ alkyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄ alkylene)substituted in the Phenyl ring, naphthyl, N-methyl-N-methoxyamino,heteroaryl, substituted heteroaryl, heteroaryl(C₁ -C₄ alkyl), orsubstituted heteroaryl(C₁ -C₄ alkyl); or pharmaceutically acceptablesalts and solvates thereof.
 10. A method of claim 9 where the mammal isa human.
 11. A method for the inhibition of neuronal proteinextravasation, comprising administering to a mammal in need thereof aneffective amount of a compound of formula: ##STR16## in which A--B is--CH--CH₂ -- or --C═CH--;R is H or C₁ -C₆ alkyl; R¹ is H or C₁ -C₄alkyl; X is --S--R², or --C(O)R³ ; R² is phenyl, substituted phenyl,phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄ alkylene) substituted in thephenyl ring, or pyridinyl; R³ is C₁ -C₆ alkyl, phenyl(C₁ -C₄ alkylene),phenyl(C₁ -C₄ alkylene) substituted in the phenyl ring, naphthyl,N-methyl-N-methoxyamino, heteroaryl, substituted heteroaryl,heteroaryl(C₁ -C₄ alkyl), or substituted heteroaryl(C₁ -C₄ alkyl); orpharmaceutically acceptable salts and solvates thereof.
 12. A method ofclaim 11 where the mammal is a human.